Amidomethyl-substituted 1-(carboxyalkyl) cyclopentyl-carbonylamino-benzazepine-N-acetic acid compounds, process and intermediate products for their preparation and pharmaceutical compositions containing them

ABSTRACT

Compounds having neutral endopeptidase (NEP) and/or human soluble endopeptidase (hSEP) inhibitory activity corresponding to the formula 1,  
                 
 
wherein the substituents R 1 , R 2 , R 3  and R 4  have the meanings given in the description and also pharmaceutical compositions containing these compounds, in particular pharmaceutical compositions suitable for treating or inhibiting cardiovascular diseases, sexual dysfunction and/or adverse conditions associated with apoptosis.

BACKGROUND OF THE INVENTION

The present invention relates to novel amidomethyl-substituted1-(carboxyalkyl)-cyclopentylcarbonylamino-benzazepine-N-acetic acidderivatives which are useful e.g. for the prophylaxis and/or treatmentof cardiovascular conditions or diseases, especially cardiacinsufficiency, in particular congestive heart failure; hypertension,including secondary forms of hypertension such as essentialhypertension, renal hypertension and/or pulmonary hypertension and/orfor the prophylaxis and/or treatment of sexual dysfunction and/or forthe prophylaxis and/or treatment of adverse conditions associated withapoptosis, and also to medicaments containing these compounds.Furthermore, the invention relates to a process for the preparation ofthe novel amidomethyl-substituted benzazepine-N-acetic acid derivativesand intermediate products of this process.

Sexual dysfunction (SD) is a significant clinical problem which canaffect both males and females. The causes of SD may be both organic aswell as psychological. Organic aspects of SD are typically caused byunderlying vascular diseases, such as those associated with hypertensionor diabetes mellitus, by prescription medication and/or by psychiatricdisease such as depression. Physiological factors include fear,performance anxiety and interpersonal conflict. SD impairs sexualperformance, diminishes selfesteem and disrupts personal relationshipsthereby inducing personal distress.

Apoptosis is closely involved in morphogenesis and histogenesis in thedevelopment process, maintenance of homeostasis, and bio-defense, and itis cell death having an important role in maintaining individual lives.When the death process regulated by genes is congenially or postnatallyhindered, apoptosis is excessively induced or inhibited to causefunctional disorders in various organs, and thus diseases. Drugs showingan apoptosis inhibitory activity can be used as agents for theprophylaxis and treatment of diseases which are thought to be mediatedby promotion of apoptosis.

Cardiovascular-active benzazepine-, benzoxazepine- andbenzothiazepine-N-acetic acid derivatives having a marked inhibitoryaction on the enzyme neutral endopeptidase (=NEP) are already known fromspecification EP 0 733 642 A1 (=U.S. Pat. No. 5,677,297). In addition,the compounds described therein also have lesser properties whichinhibit endothelin-converting enzyme (=ECE). Further favourablepharmacological properties of compounds falling within the structuralscope of EP 0 733 642 A1 are known from documents EP 0 830 863 A1 (=U.S.Pat. No. 5,783,53), WO 00/48601 A1 (=U.S. Pat. No. 6,482,820) and WO01/03699 A1 (=US-2003-0040512-A1).

Phosphonic acid substituted benzazepinone-N-acidic acid derivatives witha combined inhibitory effect on NEP and ECE are disclosed in document EP0 916 679 A1 (=U.S. Pat. No. 5,952,327).

Pharmaceutical preparations are known from specification WO 02/094176 A2which contain compounds having an advantageous combinatory action whichinhibits the metalloprotease enzymes NEP and IGS5 and have, inter alia,cardiovascular-active properties. Suitable compounds for suchcombination preparations are also compounds which fall within the scopeof specifications EP 0 733 642 A1 and EP 0 916 679 A1. The enzyme IGS5,as it is to be understood in the context of this invention, and itsphysiological role in connection with cardiovascular diseases, is knownper se from the specification WO 01/36610 A1. The aforementioned enzymeIGS5 is also known as “human soluble endopeptidase” (=hSEP).

International application no. WO 99/55726 A1 discloses that certainthiol inhibitors of ECE are useful among other things for treating orinhibiting erectile dysfunction.

European patent application no. EP 1 097 719 A1 discloses the use of NEPinhibitors for the treatment of female sexual dysfunction (=FSD).

Publication WO 02/06492 A1 discloses i.a. antibodies against andinhibitors of a specific polypeptide having soluble secretedendopeptidase (=SEP) activity.

Published U.S. patent application no. US 2003-0045449 discloses thatmatrix-metalloprotease inhibitors are useful for the treatment ofneurodegenerative diseases. Problems associated with that invention arefirst that matrix-metalloprotease inhibitors comprise a broad group ofprotease inhibitors, and second that according to the said applicationthe metalloproteases must be used in a pharmaceutical composition alsocontaining an N—NOS inhibitor.

Published U.S. patent application no. US 2002-0013307 teaches the use ofvasopeptidase inhibitors to treat or slow the progression of cognitivedysfunction and to treat and/or prevent dementia.

M. Sumitomo et al. (see Clinical Cancer Research 10 (2004) 260-266)describe the chemosensitization of androgen-independent prostate cancerwith NEP.

SUMMARY OF THE INVENTION

It was an object of the present invention to provide novel activesubstances having a combined activity profile inhibiting the enzymesNEP, hSEP and ECE.

Another object of the invention was to provide active substances whichare suitable for the prophylaxis and/or treatment of cardiovascularconditions or diseases, especially cardiac insufficiency, in particularcongestive heart failure; hypertension, including secondary forms ofhypertension such as essential hypertension, renal hypertension and/orpulmonary hypertension.

A further object of the invention was to provide active substances whichare useful for inhibiting or treating sexual dysfunction.

An additional object of the invention was to provide active substanceswhich are useful in inhibiting or treating adverse conditions associatedwith apoptosis.

These and other objects have been achieved in accordance with thepresent invention by providing a compound corresponding to the formulaI:

wherein

-   R¹ is hydrogen or a group forming a biolabile ester,-   R² is hydrogen, C₁₋₄-alkyl or C₁₋₄-hydroxyalkyl, the hydroxyl group    of which is optionally esterified with C₂₋₄-alkanoyl or an amino    acid residue, and-   R³ is C₁₋₄-alkyl; C₁₋₄-alkoxy-C₁₋₄-alkyl; C₁₋₄-hydroxyalkyl, which    is optionally substituted by a second hydroxyl group and the    hydroxyl groups of which are each optionally esterified with    C₂₋₄-alkanoyl or an amino acid residue;    (C₀₋₄-alkyl)₂amino-C₁₋₆-alkyl; C₃₋₇-cycloalkyl;    C₃₋₇-cycloalkyl-C₁₋₄-alkyl; phenyl-C₁₋₄-alkyl, the phenyl group of    which is optionally substituted once or twice by C₁₋₄-alkyl,    C₁₋₄-alkoxy or halogen; naphthyl-C₁₋₄-alkyl; C₃₋₆-oxoalkyl;    phenylcarbonylmethyl, the phenyl group of which is optionally    substituted once or twice by C₁₋₄-alkyl, C₁₋₄-alkoxy or halogen, or    2-oxoazepanyl, or-   R² and R³ together are C₄₋₇-alkylene, the methylene groups of which    are optionally replaced once or twice by carbonyl, nitrogen, oxygen    or sulphur, or which are optionally substituted once by hydroxy,    which is optionally esterified with C₂₋₄-alkanoyl or an amino acid    residue; C₁₋₄-alkyl; C₁₋₄-hydroxyalkyl, the hydroxyl group of which    is optionally esterified with C₂₋₄-alkanoyl or an amino acid    residue; phenyl or benzyl, and-   R⁴ is hydrogen or a group forming a biolabile ester,    or a physiologically acceptable salt thereof.

It has now surprisingly been found that a group according to theinvention of novel amidomethyl-substituted1-(carboxyalkyl)-cyclopentylcarbonylamino-benzazepine-N-acetic acidderivatives is distinguished by an action profile which inhibits theenzymes NEP and hSEP, and to a certain extent also ECE, and thereforeappears suitable for the prophylaxis and/or treatment of cardiovascularconditions or diseases, especially cardiac insufficiency, in particularcongestive heart failure; hypertension, including secondary forms ofhypertension such as essential hypertension, renal hypertension and/orpulmonary hypertension; and/or or for the prophylaxis and/or treatmentof sexual dysfunction and/or for the prophylaxis and/or treatment ofadverse conditions associated with apoptosis.

The invention thus relates to novel amidomethyl-substituted1-(carboxyalkyl)-cyclopentylcarbonylamino-benzazepine-N-acetic acidderivatives of the general formula I,

wherein

-   R¹ is hydrogen or a group forming a biolabile ester,-   R² is hydrogen, C₁₋₄-alkyl or C₁₋₄-hydroxyalkyl, the hydroxyl group    of which is optionally esterified with C₂₋₄-alkanoyl or an amino    acid residue, and-   R³ is C₁₋₄-alkyl; C₁₋₄-alkoxy-C₁₋₄-alkyl; C₁₋₄-hydroxyalkyl, which    is optionally substituted by a second hydroxyl group and the    hydroxyl groups of which are each optionally esterified with    C₂₋₄-alkanoyl or an amino acid residue;    (C₀₋₄-alkyl)₂amino-C₁₋₄-alkyl; C₃₋₇-cycloalkyl;    C₃₋₇-cycloalkyl-C₁₋₄-alkyl; phenyl-C₁₋₄-alkyl, the phenyl group of    which is optionally substituted 1-2 times by C₁₋₄-alkyl, C₁₋₄-alkoxy    and/or halogen; naphthyl-C₁₋₄-alkyl; C₃₋₆-oxoalkyl;    phenylcarbonylmethyl, the phenyl group of which is optionally    substituted 1-2 times by C₁₋₄-alkyl, C₁₋₄-alkoxy and/or halogen, or    2-oxoazepanyl, or-   R² and R³ together are C₄₋₇-alkylene, the methylene groups of which    are optionally replaced 1-2 times by carbonyl, nitrogen, oxygen    and/or sulfur and which are optionally substituted once by hydroxy,    which is optionally esterified with C₂₋₄-alkanoyl or an amino acid    residue; C₁₋₄-alkyl; C₁₋₄-hydroxyalkyl, the hydroxyl group of which    is optionally esterified with C₂₋₄-alkanoyl or an amino acid    residue; phenyl or benzyl, and-   R⁴ is hydrogen or a group forming a biolabile ester,    and physiologically compatible salts of acids of Formula I and/or    physiologically compatible acid addition salts of compounds of    Formula I. Furthermore, a subject of the invention is medicaments    containing the compounds of Formula I. Even further, a subject of    the invention is a process for the preparation of the compounds of    Formula I and intermediate products of this process.

Where in the compounds of Formula I or in other compounds describedwithin the context of the present invention substituents are or containC₁₋₄-alkyl, these may each be straight-chain or branched. Wheresubstituents in compounds of Formula I stand for halogen, fluorine,chlorine or bromine are suitable. Chlorine is preferred. Wheresubstituents contain C₂₋₄-alkanoyl, this may be straight-chain orbranched. Acetyl is preferred as C₂₋₄-alkanoyl.

Where in the compounds of Formula I hydroxyl groups are esterified withamino acid residues, these amino acid residues may be derived fromnatural or non-natural, α- or β-amino acids. Suitable amino acids whichcan be used are for example selected from the group cosisting ofalanine, 2-aminohexanoic acid (=norleucine), 2-aminopentanoic acid(=norvaline), arginine, asparagine, aspartic acid, cysteine,3,4-dihydroxyphenylalanine (=dopa), glutamine, glutamic acid, glycine,histidine, isoleucine, leucine, lysine, methionine, ornithine(=2,5-diaminovaleric acid), 5-oxo-2-pyrrolidine-carbonic acid(=pyroglutamic acid), phenylalanine, proline, serine, threonine,thyronine, tryptophan, tyrosine and valine. Preferred are amino acidresidues which are derived from alanine, asparagine, glutamine, glycine,isoleucine, leucine, lysine, ornithine, phenylalanine, proline andvaline.

The compounds of Formula I represent dicarboxylic acid derivativesoptionally esterified with groups forming biolabile esters. Thebiolabile esters of Formula I as a rule represent administerableprecursors (=“prodrugs”) of the free acids. Then, monoesters or diestersof the compounds of Formula I may occur. Depending on the form ofadministration, the biolabile esters or the free acids are preferred,the latter being suitable in particular for intravenous (=i.v.)administration.

Groups which can be cleaved under physiological conditions in vivo,releasing bioavailable derivatives of the compounds of Formula I, aresuitable as groups forming biolabile esters R¹ and R⁴. Suitable examplesof this are C₁₋₄-alkyl groups, in particular methyl, ethyl, n-propyl andisopropyl; C₁₋₄-alkyloxy-C₁₋₄-alkyloxy-C₁₋₄-alkyl groups, in particularmethoxyethoxymethyl; C₃₋₇-cycloalkyl groups, in particular cyclohexyl;C₃₋₇ cycloalkyl-C₁₋₄-alkyl groups, in particular cyclopropylmethyl;N,N-di-(C₀₋₄-alkyl)amino-C₁₋₆-alkyl groups; phenyl or phenyl-C₁₋₄-alkylgroups optionally substituted in the phenyl ring once or twice byhalogen, C₁₋₄-alkyl or C₁₋₄-alkoxy or by a C₁₋₄-alkylene chain bonded totwo adjacent carbon atoms; dioxolanylmethyl groups optionallysubstituted in the dioxolane ring by C₁₋₄-alkyl;C₂₋₆-alkanoyloxy-C₁₋₄-alkyl groups optionally substituted at theoxy-C₁₋₄-alkyl group by C₁₋₄-alkyl; double esters like1-[[(C₁₋₄-alkyl)carbonyl]oxy]C₁₋₄-alkyl esters, e.g.(RS)-1-[[(isopropyl)carbonyl]oxy]ethyl or(RS)-1-[[(ethyl)carbonyl]oxy]-2-methylpropyl (for preparation see e.g.F. W. Sum et al., Bioorg. Med. Chem. Lett. 9 (1999) 1921-1926 or Y.Yoshimura et al., The Journal of Antibiotics 39/9 (1986) 1329-1342);carbonate esters like 1-[[(C₄₋₇-cycloalkyloxy)carbonyl]oxy] C₁₋₄-alkylesters, preferably (RS)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl(=cilexetil; for preparation see e.g. K. Kubo et al., J. Med. Chem. 36(1993) 2343-2349, cited as “Kubo et al.” hereinafter)) or2-oxo-1,3-dioxolan-4-yl-C₁₋₄-alkyl esters which optionally contain adouble bond in the dioxolan ring, preferably5-methyl-2-oxo-1,3-dioxolen-4-yl-methyl (=medoxomil, for preparation seee.g. Kubo et al.) or 2-oxo-1,3-dioxolan-4-yl-methyl(=(methyl)ethylene-carbonate). Where the group forming a biolabile esterrepresents an optionally substituted phenyl-C₁₋₄-alkyl group, this maycontain an alkylene chain with 1 to 3, preferably 1, carbon atoms andpreferably stands for optionally substituted benzyl, in particular for2-chlorobenzyl or 4-chlorobenzyl. Where the group forming a biolabileester represents an optionally substituted phenyl group, the phenyl ringof which is substituted by a lower alkylene chain, this may contain 3 to4, preferably 3, carbon atoms and in particular be indanyl. Where thegroup forming a biolabile ester represents an optionally substitutedC₂₋₆-alkanoyloxy-C₁₋₄-alkyl group, the C₂₋₆-alkanoyl group may bestraight-chain or branched.

R¹ preferably has the meanings hydrogen, ethyl, methoxyethoxymethyl,(RS)-1-[[(isopropyl)carbonyl]oxy]ethyl,(RS)-1-[[(ethyl)carbonyl]oxy]-2-methylpropyl,(RS)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl,5-methyl-2-oxo-1,3-dioxolen-4-yl-methyl, 2-oxo-1,3-dioxolan-4-yl-methylor (RS)-1-[[(ethoxy)carbonyl]oxy]ethyl.

R² preferably has the meanings hydrogen, methyl, ethyl, 2-hydroxyethylor 3-hydroxypropyl, each hydroxyl group optionally being esterified withC₂₋₄-alkanoyl or an amino acid residue.

Where R³ has the meaning (C₀₋₄-alkyl)₂amino-C₁₋₆alkyl, one or twoC₀₋₄-alkyl groups can independently of each other be present. Morespecifically, “(C₀₋₄-alkyl)₂amino-C₁₋₆-alkyl” expressly comprises themeanings “(C₀)₂-alkylamino-C₁₋₄-alkyl”,“(C₀)(C₁₋₄)-alkylamino-C₁₋₆-alkyl” and “(C₁₋₄)₂-alkylamino-C₁₋₆-alkyl”.“(C₀)₂-alkylamino-C₁₋₆-alkyl” is meant to denominate an unsubstitutedprimary (=—NH₂) amino group bonded to C₁₋₆-alkyl(ene);“(C₀)(C₁₋₄)-alkylamino-C₁₋₆-alkyl” is meant to denominate a secondaryamino group monosubstituted by (C₁₋₄)-alkyl and bonded toC₁₋₆-alkyl(ene); “(C₁₋₄)₂-alkylamino-C₁₋₆-alkyl” is meant to denominatea tertiary amino group disubstituted by (C₁₋₄)-alkyl and bonded toC₁₋₆-alkyl(ene). R³ preferably has the meanings isopropyl; methoxyethyl;2-hydroxyethyl or 3-hydroxypropyl, each hydroxyl group optionally beingesterified with C₂₋₄-alkanoyl or an amino acid residue;3-acetyloxy-n-propyl; cyclopropylmethyl; 2-methoxy-benzyl,4-methoxybenzyl; 4-methoxyphenylethyl; 2,4-dimethoxybenzyl;1-naphthylmethyl; 3-oxo-1,1-dimethylbutyl; phenyl-2-oxoethyl;2-(4-methoxyphenyl)-2-oxoethyl; 3-(2-oxoazepanyl);(C₀₋₄-alkyl)₂amino-C₁₋₆-alkyl, in particular dimethylamino-n-propyl,(methyl)aminoethyl, amino-n-propyl, amino-n-butyl or amino-n-pentyl.

Where R² and R³ together are C₄₋₇-alkylene, the methylene groups ofwhich are optionally replaced or optionally substituted, optionally ineach case morpholine; piperidine; 4-ketopiperidine; 4-hydroxypiperidine,optionally being esterified with C₂₋₄-alkanoyl or an amino acid residueat the hydroxyl group; piperazine or pyrrolidine is preferred.

R⁴ preferably has the meanings hydrogen, C₁₋₄-alkyl, p-methoxybenzyl,N,N-di-(C₀₋₄-alkyl)amino-C₁₋₆-alkyl,(RS)-1-[[(isopropyl)carbonyl]oxy]ethyl,(RS)-1-[[(ethyl)carbonyl]-oxy]-2-methylpropyl,(RS)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl,5-methyl-2-oxo-1,3-dioxolen-4-yl-methyl, 2-oxo-1,3-dioxolan-4-yl-methylor (RS)-1-[[(ethoxy)carbonyl]oxy]-ethyl.

Particularly preferred compounds of Formula I include compounds selectedfrom the group consisting of:

-   2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-[isopropyl(methyl)amino]-4-oxobutanoic    acid (32);-   2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-(dimethylamino)-4-oxobutanoic    acid (54);-   2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-(diethylamino)-4-oxobutanoic    acid (55);-   2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-[(2-hydroxyethyl)(methyl)amino]-4-oxobutanoic    acid (43);-   2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-[(3-hydroxypropyl)(methyl)amino]-4-oxobutanoic    acid (56);-   2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-(4-hydroxypiperidin-1-yl)-4-oxobutanoic    acid (57);-   2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-oxo-4-[4-(L-valyloxy)piperidin-1-yl]butanoic    acid (68);-   2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-morpholin-4-yl-4-oxobutanoic    acid (66);-   2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}4-oxo-4-(4-oxopiperidin-1-yl)butanoic    acid (45);-   4-[bis(2-hydroxyethyl)amino]-2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-oxobutanoic    acid (58);-   2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-{ethyl[3-(ethylamino)propyl]amino}-4-oxobutanoic    acid (52),-   2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-[[2-(dimethylamino)ethyl](methyl)amino]-4-oxobutanoic    acid (59),-   4-[(3-aminopropyl)(ethyl)amino]-2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-oxobutanoic    acid (67),-   2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-{methyl[2-(methylamino)ethyl]amino}-4-oxobutanoic    acid (68),-   4-[(4-aminobutyl)(methyl)amino]-2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-oxobutanoic    acid (75),-   4-[(4-aminobutyl)(ethyl)amino]-2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-oxobutanoic    acid (76),-   2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-{methyl[3-(methylamino)propyl]amino}-4-oxobutanoic    acid (77), and-   4-[(5-aminopentyl)(methyl)amino]-2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-oxobutanoic    acid (78),    together with their biolabile esters and physiologically compatible    salts of acids of these compounds of Formula I and/or    physiologically compatible acid addition salts of these compounds of    Formula I.

According to the invention, the novel compounds of Formula I and theirsalts are obtained by reacting a compound of the general formula II,

wherein R¹⁰¹ and R⁴⁰¹, independently of each other, are each anacid-protecting group, with a compound of the general formula III,

wherein R² and R³ have the above meanings,where R² and/or R³ contain free hydroxyl groups, if desired these arereacted with a compound of the general formula IV,C₁₋₃—C(O)—X  IVwherein X stands for a leaving group, or with an amino acid derivativeprotected by a suitable protective group,where R¹⁰¹ and/or R⁴⁰¹ do not represent desired groups forming abiolabile ester and/or where R² and/or R³ comprise protective groups inany present amino acid residue, these are cleaved off in succession inthe resulting compounds simultaneously or individually in any desiredsequence and if desired the acid functions released in each case areconverted into biolabile ester groups,and if desired resulting acids of Formula I are converted into theirphysiologically compatible salts, or salts of the acids of Formula I areconverted into the free acids and/or bases of Formula I are convertedinto their acid addition salts or acid addition salts are converted intofree bases of Formula I.

Suitable physiologically compatible salts of acids of Formula I are ineach case alkali metal, alkaline-earth metal or ammonium salts thereof,for example sodium, potassium or calcium salts thereof, physiologicallycompatible, pharmacologically neutral organic salts thereof with aminessuch as for example ammonia, diethylamine, tert. butylamine,N-methylglucamine, choline, or with amino acids such as for examplearginine. Where in compounds of Formula I the substituents R² and/or R³contain basic groups, in particular nitrogen, the compounds of Formula Imay also occur in the form of acid addition salts. Physiologicallycompatible acid addition salts of compounds of Formula I are theirconventional salts with inorganic acids, for example sulfuric acid,phosphoric acid or hydrohalic acids, preferably hydrochloric acid, orwith organic acids, for example lower aliphatic monocarboxylic,dicarboxylic or tricarboxylic acids such as maleic acid, fumaric acid,tartaric acid, citric acid, or with sulfonic acids, for example loweralkanesulfonic acids such as methanesulfonic acid.

Conventional protective groups for protecting carboxylic acid functionsmay be selected as acid-protecting groups R¹⁰¹ and R⁴⁰¹, which can thenbe cleaved off again using known methods. Suitable protective groups forcarboxylic acids are known, for example, from McOmie, “Protective Groupsin Organic Chemistry”, Plenum Press (cited as “McOmie” hereinafter), andGreene, Wuts, “Protective Groups in Organic Synthesis”, WileyInterscience Publication (cited as “Greene” hereinafter), each in themost recent edition. Groups forming a biolabile ester may also be usedas acid-protecting groups.

The compounds obtained upon reaction of compounds of Formula II withcompounds of Formula III in these cases already represent esters ofFormula I according to the invention.

Suitable acid-protecting groups R¹⁰¹ and R⁴⁰¹ are in particular thosegroups which can be selectively cleaved or selectively introducedindependently of each other. Examples of acid-protecting groups whichare cleavable under different conditions, which may also representgroups forming biolabile esters, are: unbranched lower alkyl groups suchas ethyl, which can be cleaved off relatively easily under basicconditions; branched lower alkyl groups such as tert. butyl, which canbe cleaved off easily by acids such as trifluoroacetic acid;phenylmethyl groups optionally substituted in the phenyl ring such asbenzyl, which can easily be cleaved off by hydrogenolysis oralternatively under basic conditions; phenylmethyl groups substitutedone or more times in the phenyl ring by lower alkoxy, such asp-methoxybenzyl, which are cleaved relatively easily under oxidativeconditions, for example under the action of2,3-dichloro-5,6-dicyano-1,4-benzoquinone (=DDQ) or ceric ammoniumnitrate; or the known silicon-containing protective groups which caneasily be cleaved by fluoride ions. The person skilled in the art isfamiliar with selecting suitable protective groups to obtain a desiredsubstitution pattern.

The compounds of Formula I contain two chiral carbon atoms, namely thecarbon atom bearing the amide side chain in position 3 of thebenzazepine skeleton (=C_(b)*) and the carbon atom bearing the radical“—COOR¹” (=C_(a)*). The compounds can thus be present in a total of fourstereoisomeric forms. The present invention comprises both the mixturesof stereoisomers and enantiomers, and also the isomerically purecompounds of Formula I. Isomerically pure compounds of Formula I arepreferred. Particularly preferred are compounds of Formula I wherein thecarbon atom bearing the amide side chain in position 3 of thebenzazepine skeleton is in the “S” configuration. With respect to thechiral carbon atom “*C_(a)” bearing the radical “—COOR¹”, theconfiguration of the compounds of Formula I which is preferred accordingto the invention in the context of this invention is provisionallyassigned the configuration designation “rel1” (see the experimentalpart). It can be derived by analogous observations of suitable compoundsof known configuration that the preferred configuration “rel1” at thechiral center “*C_(a)” is probably likewise the “S” configuration.

The reaction of the acids of Formula II with the amines of Formula IIIcan be carried out according to conventional methods for the formationof amide groups by aminoacylation. The carboxylic acids of Formula II ortheir reactive derivatives may be used as acylation agents. Inparticular mixed acid anhydrides and acid halides are suitable reactivederivatives. Thus for example acid chlorides or acid bromides of theacids of Formula II or mixed esters of the acids of Formula II withorganic sulfonic acids, for example with lower-alkanesulfonic acidsoptionally substituted by halogen, such as methanesulfonic acid ortrifluoromethanesulfonic acid, or with aromatic sulfonic acids such asbenzenesulfonic acids or with benzenesulfonic acids substituted by loweralkyl or halogen, e.g. toluenesulfonic acids or bromobenzenesulfonicacids, can be used. The acylation may take place in an organic solventwhich is inert under the reaction conditions at temperatures between−20° C. and room temperature (=RT). Suitable solvents are halogenatedhydrocarbons such as dichloromethane or aromatic hydrocarbons such asbenzene or toluene or cyclic ethers such as tetrahydrofuran (=THF) ordioxane or mixtures of these solvents.

The acylation can expediently, in particular if a mixed anhydride of theacids of Formula II with a sulfonic acid is used as acylation agent, becarried out in the presence of an acid-binding reagent. Suitableacid-binding agents are for example organic bases which are soluble inthe reaction mixture such as tertiary nitrogen bases, for exampletert.-lower alkylamines and pyridines such as triethylamine,tripropylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine,4-diethylaminopyridine or 4-pyrrolidinopyridine. Organic bases used inexcess can also serve as solvents at the same time.

If the acids of Formula II themselves are used as acylation agents, thereaction of the amino compounds of Formula III with the carboxylic acidsof Formula II can expediently also be carried out in the presence of acoupling reagent known e.g. from peptide chemistry as being suitable foramide formation. Examples of coupling reagents which promote amideformation with the free acids by reacting with the acid in situ, forminga reactive acid derivative, are in particular: ethyl chloroformate,alkylcarbodiimides, e.g. cycloalkylcarbodiimides such asdicyclohexylcarbodiimide orN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (=EDC),carbonyldiimidazole and N-lower alkyl-2-halopyridinium salts, inparticular halides or toluenesulfonates. The reaction in the presence ofa coupling reagent can be carried out expediently at temperatures of−30° to +50° C. in solvents such as halogenated hydrocarbons and/oraromatic solvents and optionally in the presence of an acid-bindingamine described above.

In the compounds obtained by reacting the compounds of Formula II withthe compounds of Formula III, wherein R² and/or R³ contain free hydroxylgroups, these may if desired be reacted in known manner with a compoundof Formula IV. In compounds of Formula IV, the leaving group X standsfor example for halogen, preferably for chlorine.

In the compounds obtained by reacting the compounds of Formula II withthe compounds of Formula III, wherein R² and/or R³ contain free hydroxylgroups, these may if desired be reacted in known manner with an aminoacid derivative protected by a suitable protective group. Suitableprotective groups for amino acids together with methods of introducingthem or selectively cleaving them are known in the art, e.g. from McOmieor from Greene. Suitably protected amino acid derivatives are eithercommercially available or can be prepared in a known manner.

The protective groups R¹⁰¹ and R⁴⁰¹, provided that they do not representany desired groups forming a biolabile ester, and/or the protectivegroups which may be present in any present amino acid moiety in R²and/or R³, can be cleaved in known manner and if desired selectivelyfrom the compounds obtained by reacting the compounds of Formula II withthe compounds of Formula III.

Compounds of Formula I may be isolated from the reaction mixture and ifnecessary purified in known manner, for example by high-performanceliquid chromatography (=HPLC).

The starting compounds of Formula II are novel compounds which aresuitable as intermediate products for the preparation of novel activesubstances, for example for the preparation of the compounds of FormulaI. The compounds of Formula II can be prepared by reacting compounds ofthe general formula V,

wherein R⁵ is an acid-protecting group and R¹⁰¹ has the above meaning,with compounds of the general formula VI,

wherein R⁴⁰¹ has the above meaning, and subsequently cleaving off theacid-protecting groups R⁵ again in known manner. The reaction can becarried out in a manner known for aminoacylations, for examplecorresponding to the manner indicated above for the reaction ofcompounds of Formula II with compounds of Formula III. To avoidundesirable secondary reactions, it may be advantageous to cleave theacid-protecting groups R⁵ by means of a method which does not operate inalkaline medium and consequently to select correspondingly suitableacid-protecting groups R⁵.

The amines of Formula III are known per se or can be prepared in knownmanner from known compounds.

The reactive acid derivatives of Formula IV are known per se or can beprepared in known manner from known compounds. These are straight-chainor branched C₁₋₄-carboxylic acid derivatives.

Compounds of Formula V can be prepared by reacting acrylic esterderivatives of the general formula VII,

wherein R¹⁰¹ and R⁵ have the above meanings, with cyclopentanecarboxylicacid. The reaction can take place in known manner under the conditionsof a Michael condensation in an organic solvent which is inert under thereaction conditions by reaction of the cyclopentanecarboxylic acid witha strong base capable of forming the dianion of thecyclopentanecarboxylic acid and subsequent reaction with the acrylicester derivative of Formula VII. Suitable solvents are ethers, inparticular cyclic ethers such as THF. Suitable strong bases arenon-nucleophilic organic alkali metal amides or alkali metal loweralkyls such as lithium diisopropylamide or n-butyllithium. Expediently,the cyclopentanecarboxylic acid is reacted in THF with two equivalentsof n-butyllithium and the reaction mixture is then reacted further withthe compound of Formula VII. The reaction temperature may be between−80° and 0° C.

Compounds of Formula VI are known, for example from the specification EP0 733 642 A1, and can be prepared in the form of their racemates oralternatively in isomerically pure form according to the methodsdescribed therein or methods analogous thereto.

Compounds of Formula VII can be prepared by esterifying compounds of thegeneral formula VIII,

wherein R⁵ represents an acid-protecting group, in known manner with adesired alcohol.

Compounds of Formula VIII can for example obtained by reacting itaconicacid anhydride under known conditions which open the anhydride groupwith a reagent capable of formation of the acid-protecting group R⁵ suchas a correspondingly substituted alcohol.

In the reactions described above, the chiral centers in the startingcompounds of Formula V and of Formula VI are not changed, so thatdepending on the type of starting compounds finally isomerically purecompounds of Formula I or isomer mixtures can be obtained. For thepreparation of stereochemically uniform compounds of Formula I,expediently stereochemically uniform compounds of Formula V are reactedwith stereochemically uniform compounds of Formula VI. If anenantiomerically pure compound of Formula V is reacted with a racemiccompound of Formula VI or a racemic compound of Formula V with anenantiomerically pure compound of Formula VI, in each case a mixture oftwo diastereomers is obtained, which if desired can be separated at thestage of the compounds of Formula II or at the stage of the compounds ofFormula I in known manner. The reaction of racemic compounds of FormulaV with racemic compounds of Formula VI yields corresponding mixtures offour isomers, which can be separated if desired in known manner, forexample by HPLC separation on possibly chiral separating materials.

The compounds of Formula V have an asymmetric or chiral center at thecarbon atom bearing the radical “—COOR¹⁰¹” and are obtained uponsynthesis from acrylic ester derivatives of Formula VII in the form oftheir racemates. The optically active compounds can in principle beobtained from the racemic mixtures in a known manner, e.g. bychromatographic separation on chiral separating materials or by reactionwith suitable optically active bases, e.g. α-methylbenzylamine,cinchonidine or pseudoephedrine, and subsequent separation into theiroptical antipodes by fractional crystallisation of the salts obtained.

The compounds of Formula I and their pharmacologically compatible saltsare distinguished by advantageous pharmacological properties. Inparticular, the substances inhibit the enzyme NEP. NEP is an enzymewhich breaks down endogenous natriuretic peptides, e.g. atrialnatriuretic peptide (=ANP). Due to their inhibitory action on the NEPactivity, the substances are capable of improving the biologicalactivity and useful life of the natriuretic peptides which can beattacked by NEP, in particular ANP, and are therefore suitable for thetreatment of pathological conditions which are beneficially influencedby the action of such hormones, above all of cardiovascular diseases,especially cardiac insufficiency, in particular congestive heartfailure.

In congestive heart failure, a peripheral vascular resistance which isincreased by reflex occurs due to a disease-induced reduced ejectionfraction of the heart. This means that the myocardium has to startpumping against an increased afterload. This leads in a vicious cycle toincreased strain on the heart and makes the situation even worse. Theincrease in the peripheral resistance is mediated, inter alia, by thevasoactive peptide endothelin (=ET-1). Endothelin is the most powerfulcurrently-known endogenous vasoconstrictor substance and is producedfrom the precursor big endothelin (=Big-ET-1). According to what iscurrently known, various enzymes collaborate in the conversion ofBig-ET-1 to ET-1, inter alia the enzymes ECE and hSEP (see on this pointe.g. WO 02/094176).

In congestive heart failure, as a result of the decreased cardiac outputand the increase in peripheral resistance, back-pressure phenomena ofthe blood occur in the pulmonary circulation and the heart itself. As aresult, an increased wall tension of the heart muscle occurs in the areaof the auricles and chambers. In such a situation, the heart functionsas an endocrine organ and secretes, inter alia, ANP into thebloodstream. Due to its marked vasodilatory and natriuretic/diureticactivity, ANP brings about both a reduction in the peripheral resistanceand a decrease in the circulating blood volume. The consequence is amarked pre- and afterload decrease. This constitutes an endogenouscardioprotective mechanism. This positive endogenous mechanism islimited in that ANP only has a very short half-life in the plasma. Thereason for this is that the hormone is very rapidly broken down by NEP.

The compounds according to the invention reduce the production ofendothelin by inhibiting the ECE activity and additionally inhibitingthe hSEP activity and thus counteract an increase in the peripheralresistance, which consequently results in relieving myocardial strain.Results hitherto furthermore suggest that the substances according tothe invention by inhibiting the NEP activity result in higher ANP levelsand an extended duration of action of ANP. This should result inintensification of the ANP-mediated endogenous mechanism ofcardioprotective action and impart to the substances of Formula I higheffectiveness with respect to intensification of thediuretic/natriuretic ANP-induced activities.

NEP is involved not only in the breakdown of ANP but also in thebreakdown of endothelin. It follows from this that pure NEP inhibitionin addition to the desired increase in the ANP levels would also lead toan unfavourable increase in the endothelin levels. For this reason, amixed profile of NEP, hSEP and a certain proportion of ECE inhibitionshould be regarded as particularly beneficial, since it prevents boththe breakdown of the natriuretic/diuretic ANP (by NEP blockade), andsimultaneously inhibits the formation of endothelin (by hSEP and ECEinhibition). As a result, a positive influence can be brought to bear onthe adverse attendant effect of pure NEP inhibitors (namely undesirableincrease in the endothelin levels).

The combined action profile of compounds of Formula I as inhibitors ofNEP, hSEP and, to a lesser extent, also of ECE, makes the compoundsaccording to the invention appear particularly suitable for theprophylaxis and/or treatment of pathological conditions like conditionsor diseases such as cardiovascular conditions or diseases, especiallycardiac insufficiency, including acute heart failure and chronic heartfailure and in particular congestive heart failure; but alsohypertension, including secondary forms of hypertension such asessential hypertension, renal hypertension and/or pulmonaryhypertension; heart failure, angina pectoris, cardiac arrhythmias,myocardial infarction, perioperative myocardial infarction, poorprognosis myocardial infarction, cardiac hypertrophy, congestivecardiomyopathy, hypertrophic obstructive cardiomyopathy, hypertrophicnon-obstructive cardiomyopathy, idiopathic cardiomyopathy, myocarditis,pericarditis and/or endocarditis larger mammals, particularly humans.The compounds of Formula I may also be used beneficially in theprophylaxis or treatment of damage to the heart, in particular to themyocardium, induced by cardiotoxic doses of medicaments, in particularof cytostatic agents, preferably of cytostatic antibiotics or chemicals;angina abdominalis, cerebral ischaemias, peripheral vascular disease,subarachnoid haemorrhage, chronic obstructive pulmonary disease (COPD),asthma, renal disease (renal failure), atherosclerosis, and pain incases of colorectal or prostatic carcinoma in larger mammals,particularly humans.

What is striking is the surprisingly good effectiveness of the compoundsof Formula I after i.v. administration with regard to their bloodpressure-regulating action, in particular their hypotensive action.

Description of the Pharmacological Test Methods

The example numbers quoted relate to the preparation examples describedbelow.

1. In-Vitro Investigation of the NEP Inhibitory Action of the Substances

To demonstrate the inhibitory action of the substances according to theinvention on NEP, the inhibitory action of the substances on thehydrolytic breakdown of the polypeptideMca-Asp-Ile-Ala-Trp-Phe-Dpa-Thr-Pro-Glu-His-Val-Val-Pro-Tyr-Gly-Leu-Gly-COOHoccurring as a result of the enzymatic activity of NEP was investigatedin a standard test in vitro. In this test, the measure of the inhibitoryactivity of the substances which was determined was their IC₅₀ value.The IC₅₀ value of a test substance having enzyme-inhibitory activity isthat concentration of the test substance at which 50% of the enzymaticactivity of the NEP is blocked.

-   Test buffer: 100 mM Tris pH 7.0, 250 mM NaCl-   Enzyme: soluble, human recombinant NEP Prof. Crine, University of    Montreal, Canada stock solution: 100 μg/ml in 20 mM Tris pH 7.0,    Working solution: Stock solution with test buffer diluted to 2 μg/ml-   Substrate:    Mca*-Asp-Ile-Ala-Trp-Phe-Dpa**-Thr-Pro-Glu-His-Val-Val-Pro-Tyr-Gly-Leu-Gly-COOH;    a fluorescence-quenched Big-ET-1 analogon, i.e. a substrate of    metalloproteases which is detectable via the fluorescence signal, in    particular of NEP and ECE-1. The fluorescence of the MCA fluorophore    is initially quenched by the presence of the “quencher” Dpa.    -   *Mca=(7-methoxycoumarin-4-yl)    -   **Dpa=(3-[2,4-dinitrophenyl]-L-2,3-diaminopropionyl) from        Polypeptide Laboratories, Wolfenbuttel, Germany-   Stock solution: 100 μM in test buffer-   Test substances: All the substances were dissolved in DMSO (10 mM)    and diluted to the concentration to be tested with test buffer.

70 μl test buffer, 10 μl enzyme working solution and 10 μl testsubstance solution were mixed in an Eppendorf vessel and preincubated at37° C. for 15 minutes (=min.). Then 10 μl substrate stock solution wasadded and the test batch was incubated for 60 minutes at 37° C. Theenzymatic reaction was then ended by 5-minutes' heating to 95° C. Aftercentrifugation (Heraeus Biofuge B, 3 min.), the liquid supernatant wasinvestigated by HPLC in accordance with the following specifications.

The substrate was separated from cleavage products by means ofreversed-phase HPLC (CC 125/4 Nucleosil 300/5 C₁₈ RP column with CC 8/4Nucleosil 100/5 C18 precolumn, from Macherey-Nagel, Duren, Germany). Forthis, 60 μl of the test mixture was injected into the HPLC sampleinjection point and the column was then eluted at a flow rate of 1ml/min with the following gradient: Mobile Phase A: 100% H₂O + 0.5 MH₃PO₄ pH 2.0 Mobile Phase B: 100% acetonitrile + 0.5 M H₃PO₄ 0-2 min.20% B 8-10 min. 60-90% B 2-6 min. 20-60% B 10-13 min. 90% B 6-8 min. 60%B 13-15 min. 90-20% B

All the peptides were detected by absorption at 214 nm and byfluorescence with an excitation wavelength of 328 nm and an emissionwavelength of 393 nm.

Upon enzymatic cleavage of the peptide, the fluorophore (=Mca) and thequencher end up in different peptide fragments, which reduces theeffectiveness of the quench. This results in an increase influorescence. The increasing fluorescence signal (corresponds to thesurface, A) of the HPLC peak of the peptide with the non-quenched Mcafluorophore is used for the further calculations. This signal wascompared for samples with (=A_(inhib)) and without (=A_(control)) testsubstance of Formula I, and the value “% inhibition” was calculated onthe basis of the respective peak areas according to the followingformula:% inhibition=100*(1−A _(inhib) /A _(control))

All the samples were measured in duplicates and average values werecalculated therefrom. A standard inhibitor (10 nM thiorphan) and asolvent control (0.1% DMSO) were likewise measured as quality controlson each run.

In this test model the test substances of Formula I listed in thefollowing Table 1 had the IC₅₀ values given below: TABLE 1NEP-inhibiting action of the test substances in vitro Example No. IC₅₀(NEP) 3 17.9 10 37 16 20.0 17 <1 19 18.2 20 12.9 21 16.9 23 10.6 24 11.125 15.5 27 7.8 31 4.0 32 13.8 43 3.2 59 12 63 9 76 10.02. In Vitro Investigation of the hSEP-Inhibitory Action of theSubstances

To demonstrate the inhibitory action of the substances according to theinvention on hSEP, the inhibitory action of the substances on thehydrolytic breakdown of the polypeptideMca-Asp-Ile-Ala-Trp-Phe-Dpa-Thr-Pro-Glu-His-Val-Val-Pro-Tyr-Gly-Leu-Gly-COOHoccurring as a result of the enzymatic activity of the hSEP wasinvestigated in a standard test in vitro. In this test, the measure ofthe inhibitory activity of the substances which was determined was theirIC₅₀ value. The IC₅₀ value of a test substance having enzyme-inhibitoryactivity is that concentration of the test substance at which 50% of theenzymatic activity of the hSEP is blocked.

-   Test buffer: 100 mM Tris pH 7.0, 250 mM NaCl-   Enzyme: His6-tagged hSEP ectodomain    -   from Innogentics, Ghent, Belgium    -   Stock solution: 53 mg/ml in 20 mM HEPES pH 7.2, 5% glycerol,        0.005% Tween20, 100 mM NaCl, purity >99%    -   Working solution: stock solution with test buffer diluted to 10        mg/ml-   Substrate:    Mca-Asp-Ile-Ala-Trp-Phe-Dpa-Thr-Pro-Glu-His-Val-Val-Pro-Tyr-Gly-Leu-Gly-COOH;    fluorescence-quenched Big-ET-1 analogon.    -   Stock solution: 100 μM in test buffer from Polypeptide        Laboratories, WolfenbUttel, Germany-   Test substances: All the substances were dissolved in DMSO (10 mM)    and diluted to the concentration to be tested with test buffer.

The test and the HPLC procedure were carried out analogously to themanner set forth above for determining the in vitro inhibitory action ofthe test substances on NEP. 10 nM phosphoramidon served as standardinhibitor in the HPLC procedure. In this test model the test substancesof Formula I listed in the following Table 2 had the IC₅₀ values givenbelow: TABLE 2 hSEP-inhibiting action of the test substances in vitroExample No. IC₅₀ (hSEP) 2 21.4 3 7.8 10 25.3 16 15.0 17 24.0 19 9.5 2036.3 23 17.3 24 27.0 25 3.4 27 26.8 28 11.9 31 12.3 43 2.9 56 2.5 59 4.076 4.03. In Vivo Investigation of the Inhibitory Action of the Substances onthe Formation of ET-1 from Big-ET-1 in Rats

To demonstrate the inhibitory action of the substances according to theinvention on the formation of ET-1 from Big-ET-1, the inhibitory actionof the test substances on the hydrolytic breakdown of Big-ET-1 to ET-1occurring as a result of the enzymatic activity of ECE and relatedenzymes such as hSEP was investigated in a standard test in vivo. ET-1is an endogenous strongly vasoconstrictor substance. An increase in theET-1 level results in an increase in blood pressure. Upon infusion ofBig-ET-1, an increase in blood pressure takes place to the extent thatET-1 is produced therefrom by enzyme-catalysed cleavage of Big-ET-1. Asa measurement of the enzyme-inhibiting action of the substances, theirinhibitory action on the increase in blood pressure induced by infusionof Big-ET-1 was determined.

Rats (Sprague-Dawley, CRLD=Charles River) were anaesthetised with 1ml/kg Rompun/Ketavet 1:1. A pressure transducer (Statham) was insertedinto the carotid artery to measure blood pressure. One jugular vein wascannulated for administering the substance, and the other foradministering Big-ET-1. After a 20-minute rest phase, the rats wereadministered the corresponding test substance of Formula I in aconcentration as a rule of 10 μmol/kg, or a vehicle. Five minutes later,0.5 nmol/kg Big-ET-1 was infused over a period of one minute. Thesystolic (SAP=systolic arterial pressure) and the diastolic(DAP=diastolic arterial pressure) blood pressure and the heart rate wereeach measured before administration of the substance or beforeadministration of Big-ET and in each case every five minutes over aperiod of 30 minutes after Big-ET administration using the pressuretransducer in known manner. The maximum Big-ET-induced increase in bloodpressure and the maximum lowering of heart rate were calculated from themeasured values as the difference between the value measured at themoment of maximum development of the Big-ET action (typically after 5min.) and the value measured before Big-ET infusion. Furthermore, theintegral of the blood pressure curve under the influence of Big-ET-1 wasdetermined over 30 minutes (AUC=area under the curve). The AUC valueprovides information about the entire extent and duration of the Big-ETaction or the reduction thereof by substances; the AUC value cantherefore—in addition to the maximum Big-ET action—provide additionalinformation about the effect of the substances, for example in the eventthat the substances e.g. do not, or only slightly, influence the maximumBig-ET action, but considerably accelerate the subsiding of this action.

The percentage inhibition of the maximum Big-ET-1 effect on the systolicarterial blood pressure (SAP) after i.v. administration of the testsubstances compared with administration of a vehicle is set forth in thefollowing Table 3: TABLE 3 In vivo investigation of the antihypertensiveproperties of the test substances. % substance-related inhibition of themaximum Example No. Big-ET effect on SAP vs. control 2 −53 3 −94 4 −95 8−113 14 −59 (3 μmole) 16 −45 17 −46 20 −67 21 −43 23 −40 24 −54 26 −5329 −49 32 −52 34 −78 35 −63 38 −48 (3 μmole) 44 −75 59 −98 67 −109 68−108 75 −52 (3 μmole) 76 −93

The compound of Formula I also exhibit ECE-inhibitory properties to acertain extent. The ECE-inhibitory properties of the substances ofFormula I can be demonstrated in a standard test in vitro.

The compounds of Formula I are dually acting compounds which are capableof inhibiting NEP and hSEP and are also suited for prophylaxis and/ortreatment of SD.

In the clinic, SD disorders have been divided into female sexualdysfunction (FSD) disorders and male sexual dysfunction (MSD) disorders(see Melman, A. & Gingell, J. C. (1999). The epidemiology andpathophysiology of erectile dysfunction. J Urology 161: 5-11,hereinafter cited as “Melman et al. 1999”). The dually acting compoundsof the invention which are capable of inhibiting NEP and hSEP, inparticular the compounds of Formula I, are particularly beneficial forthe prophylaxis and/or treatment of MSD (e.g. male erectiledysfunction-MED). A further advantage of the compounds of Formula I inthis indication is a certain ECE inhibitory share at their profile ofaction.

MSD is generally associated with erectile dysfunction, also known asmale erectile dysfunction (=MED) (see Benet, A. E. et al (1994), Maleerectile dysfunction assessment and treatment options. C07Sp. TheY. 20:669-673) hereinafer cited as “Benet et al. 1994”). MED is defined as: “.. . the inability to achieve and/or maintain a penile erection forsatisfactory sexual performance (see NIH Consensus Development Panel onImpotence (1993). NIH Consensus Conference Impotence. JA. M. A. 270: 83). . . ”. It has been estimated that the prevalence of erectiledysfunction (=ED) of all degrees (minimal, moderate and completeimpotence) is 52% in men 40 to 70 years old, with higher rates in thoseolder than 70 (Melman et al. 1999). The condition has a significantnegative impact on the quality of life of the patient and their partner,often resulting in increased anxiety and tension which leads todepression and low self esteem. Whereas two decades ago, MED wasprimarily considered to be a psychological disorder (Benet et al. 1994),it is now known that for the majority of patients there is an underlyingorganic cause. As a result, much progress has been made in identifyingthe mechanism of normal penile erection and the pathophysiology of MED.

When the dually acting compounds capable of inhibiting NEP and hSEP ofthe invention, in particular the compounds of Formula I, are used in thetherapy of FSD, therapy of female sexual arousal disorder (=FSAD) ispreferred.

FSD is best defined as the difficulty or inability of a woman to findsatisfaction in sexual expression. FSD is a collective term for severaldiverse female sexual disorders (Leiblum, S. R. (1998). Definition andclassification of female sexual disorders. Int. J. Impotence Res., 10,S104-S106; Berman, J. R., Berman, L.& Goldstein, I. (1999). Femalesexual dysfunction: Incidence, pathophysiology, evaluations andtreatment options. Urology, 54, 385-391.). The woman may have lack ofdesire, difficulty with arousal or orgasm, pain with intercourse or acombination of these problems. Several types of disease, medications,injuries or psychological problems can cause FSD. Treatments indevelopment are targeted to treat specific subtypes of FSD,predominantly desire and arousal disorders. The categories of FSD arebest defined by contrasting them to the phases of normal female sexualresponse: desire, arousal and orgasm (Leiblum, S. R. (1998). Definitionand classification of female sexual disorders. Int. J. Impotence Res.,10, S104-S106).

Desire or libido is the drive for sexual expression. Its manifestationsoften include sexual thoughts either when in the company of aninterested partner or when exposed to other erotic stimuli.

Arousal is the vascular response to sexual stimulation, an importantcomponent of which is genital engorgement and includes increased vaginallubrication, elongation of the vagina and increased genitalsensation/sensitivity.

Orgasm is the release of sexual tension that has culminated duringarousal. hence, FSD occurs when a woman has an inadequate orunsatisfactory response in any of these phases, usually desire, arousalor orgasm.

FSD categories include hypoactive sexual desire disorder, sexual arousaldisorder, orgasmic disorders and sexual pain disorders.

Although the compounds of the invention will improve the genitalresponse to sexual stimulation (as in female sexual arousal disorder),in doing so they may also improve the associated pain, distress anddiscomfort associated with intercourse and so treat other female sexualdisorders. Thus, in accordance with a particular aspect of theinvention, there is provided use of a compound of the invention in thepreparation of a medicament for the treatment or prophylaxis ofhypoactive sexual desire disorder, sexual arousal disorder, orgasmicdisorder and sexual pain disorder, more preferably for the treatment orprophylaxis of sexual arousal disorder, orgasmic disorder, and sexualpain disorder, and preferably in the treatment or prophylaxis of sexualarousal disorder. Hypoactive sexual desire disorder is present if awoman has no or little desire to be sexual, and has no or few sexualthoughts or fantasies. This type of FSD can be caused by lowtestosterone levels, due either to natural menopause or to surgicalmenopause. Other causes include illness, medications, fatigue,depression and anxiety.

FSAD is characterized by inadequate genital response to sexualstimulation. The genitalia do not undergo the engorgement thatcharacterizes normal sexual arousal. The vaginal walls are poorlylubricated, so that intercourse is painful. Orgasms may be impeded.Arousal disorder can be caused by reduced estrogen at menopause or afterchildbirth and during lactation, as well as by illnesses, with vascularcomponents such as diabetes and atherosclerosis. Other causes resultfrom treatment with diuretics, antihistamines, antidepressants e.g.selective serotonin re-uptake inhibitors (=SSRIs) or antihypertensiveagents.

Sexual pain disorders (includes dyspareunia and vaginismus) ischaracterized by pain resulting from penetration and may be caused bymedications which reduce lubrication, endometriosis, pelvic inflammatorydisease, inflammatory bowel disease or urinary tract problems. Theprevalence of FSD is difficult to gauge because the term covers severaltypes of problem, some of which are difficult to measure, and becausethe interest in treating FSD is relatively recent.

Many women's sexual problems are associated either directly with thefemale ageing process or with chronic illnesses such as diabetes andhypertension. Because FSD consists of several subtypes that expresssymptoms in separate phases of the sexual response cycle, there is not asingle therapy.

Current treatment of FSD focuses principally on psychological orrelationship issues. Treatment of FSD is gradually evolving as moreclinical and basic science studies are dedicated to the investigation ofthis medical problem. Female sexual complaints are not all psychologicalin pathophysiology, especially for those individuals who may have acomponent of vasculogenic dysfunction (e.g. FSAD) contributing to theoverall female sexual complaint. There are at present no drugs licensedfor the treatment of FSD. Empirical drug therapy includes oestrogenadministration (topically or as hormone replacement therapy), androgensor mood-altering drugs such as buspirone or trazodone. These treatmentoptions are often unsatisfactory due to low efficacy or unacceptableside effects. Since interest is relatively recent in treating FSDpharmacologically, therapy consists of the following: psychologicalcounselling, over-the-counter sexual lubricants, and investigationalcandidates, including drugs approved for other conditions. Thesemedications consist of hormonal agents, either testosterone orcombinations of oestrogen and testosterone and more recently vasculardrugs, that have proved effective in MED. None of these agents has yetbeen demonstrated to be effective in treating FSD.

The Diagnostic and Statistical Manual (DSM) IV of the AmericanPsychiatric Association defines FSAD as being: “. . . a persistent orrecurrent inability to attain or to maintain until completion of thesexual activity adequate lubrication-swelling response of sexualexcitement. The disturbance must cause marked distress or interpersonaldifficulty . . . ”. The arousal response consists of vasocongestion inthe pelvis, vaginal lubrication and expansion and swelling of theexternal genitalia. The disturbance causes marked distress and/orinterpersonal difficulty. Studies investigating sexual dysfunction incouples reveals that up to 76% of women have complaints of sexualdysfunction and that 30-50% of women in the USA experience FSD (Berman,J. R., Berman, L. A., Werbin, T. J. et al. (1999). Female sexualdysfunction: Anatomy, physiology, evaluation and treatment options. CurrOpin Urology, 9, 563-568). FSAD is a highly prevalent sexual disorderaffecting pre-, peri- and post-menopausal (hormone replacement therapy(HRT)) women. It is associated with concomitant disorders such asdepression, cardiovascular diseases, diabetes and urogenital disorders.The primary consequences of FSAD are lack of engorgement/swelling, lackof lubrication and lack of pleasurable genital sensation. The secondaryconsequences of FSAD are reduced sexual desire, pain during intercourseand difficulty in achieving an orgasm. It has recently been hypothesisedthat there is a vascular basis for at least a proportion of patientswith symptoms of FSAD (Goldstein et al., Int. J. Impot. Res., 10,S84-S90, 1998) with animal data supporting this view (Park et al., Int.J. Impot. Res., 9,27-37,1997).

It is known that inhibitors of SEP enhance pelvic nerve-stimulated andvasoactive intestinal peptide (=VIP)-induced increases in vaginal andclitoral blood flow. It is also known that SEP inhibitors enhance VIPand nerve-mediated relaxations of the isolated vagina wall. Thus thepresent invention is advantageous as it helps provide a means forrestoring a normal sexual arousal response-namely increased genitalblood flow leading to vaginal, clitoral and labial engorgement. Thiswill result in increased vaginal lubrication via plasma transudation,increased vaginal compliance and increased genital sensitivity. Hence,the present invention provides a means to restore, or potentiate, thenormal sexual arousal response. By female genitalia herein it is meant:“The genital organs consist of an internal and external group. Theinternal organs are situated within the pelvis and consist of ovaries,the uterine tubes, uterus and the vagina. The external organs aresuperficial to the urogenital diaphragm and below the pelvic arch. Theycomprise the mons pubis, the labia majora and minora pudendi, theclitoris, the vestibule, the bulb of the vestibule, and the greatervestibular glands” (Gray's Anatomy, C. D. Clemente, 13th AmericanEdition). R. J. Levin teaches that, because “. . . male and femalegenitalia develop embryologically from the common tissue anlagen, [that]male and female genital structures are argued to be homologues of oneanother. Thus the clitoris is the penile homologue and the labiahomologues of the scrotal sac . . . ” (Levin, R. J. (1991), Exp. Clin.Efzdocrinol., 98, 6169).

With regard to MSD, in particular to MED, penile erection is ahaemodynamic event which is dependent upon the balance of contractionand relaxation of the corpus cavernosal smooth muscle and vasculature ofthe penis (see Lerner, S. E. et al (1993). A review of erectiledysfunction: new insights and more questions. J. Urology 149:1246-1255). Corpus cavernosal smooth muscle is also referred to hereinas corporal smooth muscle or in the plural sense corpus cavernosa.Relaxation of the corpus cavernosal smooth muscle leads to an increasedblood flow into the trabecular spaces of the corpus cavernosa, causingthem to expand against the surrounding tunica and compress the drainingveins. This produces a vast elevation in cavernosal blood pressure whichresults in an erection (see Naylor, A. M. (1998). Endogenousneurotransmitters mediating penile erection. Br. J. Urology 81:424-431), hereinafter cited as “Naylor, 1998”). The changes that occurduring the erectile process are complex and require a high degree ofcoordinated control involving the peripheral and central nervoussystems, and the endocrine system (Naylor, 1998). Corporal smooth musclecontraction is modulated by sympathetic noradrenergic innervation viaactivation of postsynaptic α-adrenoceptors. MED may be associated withan increase in the endogenous smooth muscle tone of the corpuscavernosum. However, the process of corporal smooth muscle relaxation ismediated partly by non-adrenergic, non-cholinergic (=NANC)neurotransmission. There are a number of other NANC neurotransmittersfound in the penis, other than nitric oxide (=NO), such as calcitoningene related peptide (=CGRP) and VIP. The main relaxing factorresponsible for mediating this relaxation is NO, which is synthesisedfrom L-arginine by nitric oxide synthase (=NOS) (see e.g. Taub, H. C. etal (1993). Relationship between contraction and relaxation in human andrabbit corpus cavernosum. Urology 42: 698-704). It is thought thatreducing corporal smooth muscle tone may aid NO to induce relaxation ofthe corpus cavernosum. During sexual arousal in the male, NO is releasedfrom neurones and the endothelium and binds to and activates solubleguanylate cyclase (sGC) located in the smooth muscle cells andendothelium, leading to an elevation in intracellular cyclic guanosine3′,5′-monophosphate (cGMP) levels. This rise in cGMP leads to arelaxation of the corpus cavernosum due to a reduction in theintracellular calcium concentration ([Ca2+] i), via unknown mechanismsthought to involve protein kinase G activation (possibly due toactivation of Ca²⁺ pumps and Ca²⁺-activated K⁺-channels).

Recently it has been shown that c-type natriuretic peptide (=CNP) mayalso play a role in MED, acting at the membrane-bound guanylyl cyclase B(=GC-B) which is expressed in human corpus cavernosum tissue.Stimulation of GC-B leads to an increase in intracellular cGMP and,consequently, smooth muscle relaxation. PDE5-inhibitors, e.g. sildenafilincrease intracellular cGMP in corpus cavernosum tissue by inhibitingits breakdown. PDE5-inhibitors are inactive in the absence of astimulator of cGMP formation, e.g. in the absence of NO. This findingsuggests that the basal (unstimulated) rate of cGMP formation in thecorpus cavernosum is rather low, so that inhibition of cGMP breakdown byPDE5 inhibitors is not sufficient for an erectile response withoutconcomittant stimulation of guanylyl cyclase. Increasing theconcentration of CNP leads to elevated intracellular cGMP concentration,by an increase in cGMP formation. Consequently, elevating the CNPconcentration in the corpus cavernosum will presumably have similareffects as inhibiting PDE5. Due to their different mechanisms of action,i.e. increasing formation of cGMP vs. inhibition of its breakdown, theapproaches of inhibiting PDE5 or the breakdown of CNP, respectively aredeemed to be additive thus making it a reasonable assumption that acombination of these two mechanisms of action will be particularlyeffective in patients who do not respond to the administration of PDE5inhibitors alone.

VIP positive nerve fibres have been found in the trabecular meshwork ofthe corpus cavernosum, suggesting a role of VIP release in penileerection. Effects of VIP are thought to be mediated via increases incAMP and are thus complementary to those of cGMP-elevating agents. Inpatients with ED an intracavernosal injection of VIP (combined with theα-adrenoceptor antagonist phentolamine) was found to be a safe andeffective treatment, with a response rate of 67% (erections sufficientfor sexual intercourse).

The endopeptidases NEP and hSEP both degrade CNP and VIP and therebylimit the effects of CNP and VIP on cavernosal smooth muscle. Inhibitionof CNP and VIP breakdown will lead to increased availability of thesevasorelaxing factors thereby increasing blood flow to the corpuscavernosum which finally should result in improved erectile function.Support can be found for this from experimental data in rabbits, showinga significant increase in intracavernosal pressure and female genitalblood flow after application of an NEP-inhibitor (see document WO02/079143). Furthermore, a gene (SMR1) encoding a pro-peptide of theendogenous NEP-inhibitor sialorphine was found (see User H. M., ZelnerD. J., McKenna K. E., McVary K. T. (2003). Microarray analysis anddescription of SMR1 gene in rat penis in a post-radical prostatectomymodel of erectile dysfunction. J Urol.; 170(1):298-301) to be markedlydownregulated (>80-fold) in a rat model of neurogenic erectiledysfunction suggesting that in this disease NEP activity may be enhancedand contribute to the development of erectile dysfunction.

Description of the Pharmacological Test Method

The example numbers quoted relate to the preparation examples describedbelow. The inhibition of the enzymatic breakdown of CNP and VIP by thecompounds used according to the invention was measured in an enzymaticin vitro assay according to the following protocol:

-   Enzymes:    -   a) hSEP (sol hu)(his)₆; or: His6-tagged hSEP ectodomain. stock        solution: 53 μg/ml in 20 mM HEPES pH 7.2, 5% glycerol, 0.005%        Tween20, 100 mM NaCl, purity >99% working solution: stock        solution diluted with assay buffer to 5 μg/ml Supplier:        Innogenetics, Ghent, Belgium. Preparation and purification of        the protein were performed as described in WO 02/094176.    -   b) NEP (prepared from pig kidney cortex) stock solution: 120        μg/ml in 20 mM bisTris, purity >95% working solution: stock        solution diluted with assay buffer to 5 μg/ml Supplier: Dr.        Philippe Crine, Univ. of Montreal, Canada-   Substrates: a) VIP    -   b) CNP (32-53)        -   stock solution: 100 μM in assay buffer        -   Supplier: Bachem, Weil am Rhein, Germany-   Assay buffer: 100 mM Tris pH 7.0, 250 mM NaCl

All test compounds were dissolved in DMSO at 10 mM and further dilutedwith assay buffer.

Activity Assay Procedure

80 μl of assay buffer, 10 μl of enzyme working solution (NEP or hSEP)and 10 μl of peptide stock solution (VIP or CNP) were mixed in anEppendorf vial and incubated for 120 min. at 37° C. The enzymaticreaction was subsequently terminated by heating to 95° C. for 5 min.After centrifugation (Heraeus Biofuge B, 3 min) the supernatant wassubjected to HPLC.

Inhibition Assay Procedure

70 μl of assay buffer, 10 μl of enzyme working solution (NEP or hSEP)and 10 μl of a test compound solution were mixed in an Eppendorf vialand preincubated at 37° C. for 15 minutes. Then, 10 μl of peptide stocksolution (VIP or CNP) was added and the reaction mixture was incubatedat 37° C. for 60 min. to allow enzymatic hydrolysis. The enzymaticreaction was subsequently terminated by heating to 95° C. for 5 min.After centrifugation (Heraeus Biofuge B, 3 min) the supernatant wassubjected to HPLC. In order to separate the remaining substrate from thecleavage products, a reversed phase HPLC technique with a CC 125/4Nucleosil 300/5 C₁₈ RP column and a CC 8/4 Nucleosil 100/5 C18 precolumn(Macherey-Nagel, Düren, Germany) was used. 60 μl of the reaction sampleswere injected into the HPLC and the column was eluted at a flow rate of1 ml/min with the following gradient: Solution A: 100% H2O + 0.5 M H3PO4pH 2.0 Solution B: 100% acetonitrile + 0.5 M H3PO4 0-2 min: 5% B  8-10min: 90% B 2-7 min: 5-50% B 10-12 min: 90-5% B 7-8 min: 50-90% B

All peptides were detected by absorbance at 214 nm (UV spectroscopy).

The percentage (=%) of hydrolysis was calculated on the basis of thepeak area of the undegraded peptide for an enzyme containing sample Y incorrelation to a sample containing the same concentration of peptidewithout enzyme (blank) by the following equation:% hydrolysis=100*(blank−Y)

Basis of the calculation of % inhibition is the peak area of theundegraded peptide (VIP or CNP) for an inhibitor containing sample X incomparison to samples containing only peptide (blank) or peptide andenzyme without inhibitor (control) according to the following equation:% inhib=100*(X−control)/(blank−control)

All samples were run in duplicate and mean values were used. A solventcontrol (0.1% DMSO) was added to each assay run. CNP and VIP werecleaved by NEP and hSEP in vitro. Breakdown of both peptides was fasterwith hSEP than with NEP, as is shown in the following Table 4. TABLE 4Breakdown rates of VIP and CNP by NEP or hSEP breakdown of CNP breakdownof VIP hSEP NEP hSEP NEP degradation 46% 39% 36% 28% at t = 2 h

The test compounds according to the invention were able to preventdegradation of CNP and VIP by both NEP and SEP. In this test model thetest substances of Formula I listed in Table 5 below had the IC₅₀ valuesgiven below: TABLE 5 Prevention of degradation of CNP and VIP by thetest compounds inhibition of breakdown of CNP breakdown of VIP breakdownby hSEP NEP hSEP NEP example no. IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM)4 1.0 10.1 3.1 3.1

The compounds of Formula I are also suited for the prophylaxis and/ortreatment of adverse conditions associated with apoptosis. Examples ofadverse conditions associated with apoptosis include:

-   -   neuro-degenerative disorders such as e.g. ischemic stroke,        cerebral ischemia, traumatic brain injury, acute disseminated        encephalomyelitis, amyotrophic lateral sclerosis (ALS),        retinitis pigmentosa, mild cognitive impairment, Alzheimer's        disease, Pick's disease, senile dementia, progressive        supranuclear palsy, subcortical dementias, Wilson disease,        multiple infarct disease, arteriosclerotic dementia, AIDS        associated dementia, cerebellar degeneration, spinocerebellar        degeneration syndromes, Friedreichs ataxia, ataxia        telangiectasia, epilepsy related brain damage, spinal cord        injury, restless legs syndrome, Huntington's disease and        Parkinson's disease, striatonigral degeneration, cerebral        vasculitis, mitochondrial encephalo-myopathies, neuronal ceroid        lipofuscinosis, spinal muscular atrophies, lysosomal storage        disorders with central nervous system involvement,        leukodystrophies, urea cycle defect disorders, hepatic        encephalopathies, renal encephalopathies, metabolic        encephalopathies, porphyria, bacterial or viral meningitis and        meningoencephalitis, prion diseases, poisonings with neurotoxic        compounds, Guillain Barre syndrome, chronic inflammatory        neuropathies, polymyositis, dermatomyositis, radiation-induced        brain damage; gastrointestinal disorders like irritable bowel        disease and inflammatory bowel diseases, Crohn's disease and        ulcerative colitis, coeliac disease, Helicobacter pylori        gastritis and other infectious gastritides, necrotizing        enterocolitis, pseudomembranous enterocolitis, radiation-induced        enterocolitis, lymphocytic gastritis, graft-versus-host disease,        acute and chronic pancreatitis;    -   hepatic diseases such as e.g. alcoholic hepatitis, viral        hepatitis, metabolic hepatitis, autoimmune hepatitis,        radiation-induced hepatitis, liver cirrhosis, hemolytic uremic        syndrome, glomerulonephritis, lupus nephritis,    -   viral diseases such as fulminant hepatitis;    -   joint-diseases such as trauma and osteoarthritis;    -   immuno-suppression or immunodeficiency, in particular autoimmune        diseases like idiopathic inflammatory myopathy, chronic        neutropenia, thrombotic thrombocytopenic purpura, rheumatoid        arthritis, idiopathic thrombocytopenic purpura, autoimmune        haemolytic syndromes, antiphospholipid antibody syndromes,        myocarditis, multiple sclerosis and its diagnostic        sub-classifications relapsing-remitting multiple sclerosis,        secondary progressive multiple sclerosis, primary progressive        multiple sclerosis, progressive relapsing multiple sclerosis,        acute multiple sclerosis, benign relapsing multiple sclerosis or        asymptomatic multiple sclerosis, neuromyelitis optica (Devic's        syndrome), lymphocytic hypophysitis, Grave's disease, Addison's        disease, hypoparathyroidism, type 1 diabetes, systemic lupus        erythematodes, pemphigus vulgaris, bullous pemphigoid, psoriatic        arthritis, endometriosis, autoimmune orchitis, autoimmune        erectile dysfunction, sarcoidosis, Wegener's granulomatosis,        autoimmune deafness, Sjögren's disease, autoimmune        uveoretinitis, interstitial cystitis, Goodpasture's syndrome and        fibromyalgia;    -   myelodysplasias such as aplastic anemia;    -   dermatological diseases including pemphigous vulgaris,        dermatomyositis, atopic dermatitis, Henoch-Schonlein purpura,        acne, systemic sclerosis, seborrhoeic keratosis, cutaneous        mastocytosis, chronic proliferative dermatitis, dyskeratosis,        scleroderma, interstitial granulomatous dermatitis, psoriasis,        bacterial infections of the skin, dermatomycoses, lepra,        cutaneous leishmaniasis, vitiligo, toxic epidermal necrolysis,        Steven Johnson syndrome, sebaceous adenoma, alopecia,        photodamage of the skin, lichen sclerosus, acute cutaneous        wounds, incontinentia pigmenti, thermal damage of the skin,        exanthematous pustulosis, lichenoid dermatosis, cutaneous        allergic vasculitis, cytotoxic dermatitis;    -   diseases of the inner ear such as e.g. acoustic trauma-induced        auditory hair cell death and hearing loss, aminoglycoside        induced auditory hair cell death and hearing loss, ototoxic        drug-induced hearing loss, perilymphatic fistula, cholesteatoma,        cochlear or vestibular ischemia, Meniere's disease,        radiation-induced hearing loss, hearing loss induced by        bacterial or viral infections and idiopathic hearing loss;    -   transplantation: graft-versus-host disease, acute and chronic        rejection of heart-, lung-, kidney-, skin-, corneal-, bone        marrow- or liver-transplants;    -   wound healing and tissue rejection.

The usefulness of the amidomethyl-substituted1-(carboxyalkyl)-cyclopentylcarbonylamino-benzazepine-N-acetic acidderivatives of Formula I for the prophylaxis and treatment of saidadverse conditions associated with apoptosis can be demonstrated insuitable animal models predictive of anti-apoptotic activity.

Description of the Pharmacological Test Methods

The example numbers quoted relate to the preparation examples describedbelow.

1. Traumatic Brain Injury: Delayed Apoptotic Neuronal Death

Contusing device. The contusing device consisted of a stainless steeltube, 40 cm in length, perforated at 1 cm intervals to prevent aircompression in the tube. Adult Wistar rats, 230-270 g, were anesthetizedwith chloral hydrate, 400 mg/kg i.p., a craniotomy over the righthemisphere was made, the device guiding a falling weight onto thefootplate resting upon the surface of the dura was placed perpendicularto the surface of the skull, and a force of 380 g×cm produced by a 20 gweight was selected to produce brain contusion. A maximum of 2.5 mmdepression of the brain surface was allowed to avoid mechanical punctureof the dura. The center of the footplate was stereotaxically positioned1.5 mm posterior and 2.5 mm lateral to the bregma. The rats underwentperfusion fixation 3 days after brain injury with a solution containing4% paraformaldehyde in phosphate buffer.

Intracerebroventricular injections: Compounds were administeredintracerebro-ventricularly (=i.c.v.) by means of a Hamilton syringe in avolume of 5-15 μl. Injections were performed over 5 min, 15 min-8 hrsafter trauma using the following stereotaxic coordinates: AP=−0.5 mm,L=−2 mm and V=−5.5 in relation to bregma (Swanson, L. W. (1992) BrainMaps: Structure of the Rat Brain, Elsevier, Amsterdam).

Morphometric analysis in hippocampus. The damage in the hippocampal CA3subfield was determined stereologically at 5 different rostrocaudallevels extending from 10.21 to 11.21 mm (Swanson, L. W. (1992) BrainMaps: Structure of the Rat Brain, Elsevier, Amsterdam) and throughoutits mediolateral axis three days after traumatic injury. Toquantitatively assess neuronal loss in the hippocampus, stereologicaldisector technique (Cruz-Orive, L. M. & Weibel, E. R. (1990) Am. J.Physiol. 258, L148-L156) was used to estimate numerical density (Nv) ofpyramidal neurons. An unbiased counting frame (0.05 mm×0.05 mm; disectorheight 0.01 mm) and a high-aperture objective (×40) were used forsampling. Normal neurons were identified by the presence of the typicalnuclei with clear nucleoplasm and distinct nucleolus surrounded bycytoplasm containing Nissl substance. The border between CA2 and CA3subfields was considered as the point where the looser arrangement oflarge pyramidal cells goes into densely packed pyramidal cells of thesubfield CA3. An arbitrary line connecting the lateral ends of thedentate granule cell layers was considered a junction between subfieldsCA3 and CA4.

In this test model the test substance of Example 3 elicited adose-dependent neuroprotective effect. A neuroprotective effect wasstill evident when the test substance of Example 3 was administeredi.c.v. up to 8 hrs after trauma:

Dose response of the neuroprotective effect of the test substance ofExample 3 when administered i.c.v. 15 min after trauma to adult Wistarrats was measured. Neuronal densities were determined in the CA3hippocampal subfield as described in the methods. Densities of CA3neurons ± Standard Error of Measurement (=SEM) in 6 stereotactic levelsin the left non-traumatized side of vehicle treated rats and thetraumatized right side of vehicle treated rats and in rats treated withthe test substance of Example 3 were measured and the results listed intable 6 below.

In all of the following tables the numbers (“n”) indicate the number ofrats per group, where applicable. TABLE 6 Neuronal densities CA3hippocampus, cells × 10³/mm³ Stereo- Compound of Compound of Compound oftactic Vehicle left; Vehicle right; Ex. 3, 3 μg; Ex. 3, 10 μg; Ex. 3, 30μg level (n = 10) (n = 10) (n = 10) (n = 10) (n = 10) 10.21 159.00 ±3.62 91.20 ± 7.60 98.40 ± 4.39 108.60 ± 4.30 108.40 ± 3.15  10.41 158.20± 3.03 87.20 ± 8.17 89.00 ± 5.05 108.60 ± 5.34 105.20 ± 5.76  10.61157.20 ± 2.88 66.80 ± 7.68 72.80 ± 6.01 111.40 ± 7.09 94.20 ± 5.10 10.81159.60 ± 2.99 56.80 ± 5.96 84.20 ± 6.47 112.00 ± 6.42 83.20 ± 7.10 11.01152.40 ± 2.99 51.40 ± 6.89 86.00 ± 7.44 111.40 ± 7.11 80.20 ± 7.45 11.21151.60 ± 2.47 71.60 ± 8.22 95.40 ± 6.96 119.20 ± 3.70 90.00 ± 9.24

Injection of vehicle resulted in the decrease of neuronal densities inthe CA3 hippocampus up to 35% of control values, while injection of 3,10 or 30 μg of the test substance of Example 3 partially preventedhippocampal neuronal loss, with the dose of 10 μg being most effective.Analysis of variance (“ANOVA”) revealed that there was a significantprotective effect of treatment on neuronal loss in the CA3 hippocampusfor all three tested doses of the test substance of Example 3 (P<0.001;n=10 per group). ANOVA also revealed that the dose of 10 μg conferredsignificantly better neuroprotection than the doses of 3 μg or 30 μg.

The time window of the neuroprotective effect of test substance ofExample 3 when administered i.c.v. 2, 4 or 8 hrs after trauma to adultWistar rats was measured. Neuronal densities were determined in the CA3hippocampal subfield as described in the methods. Densities of CA3neurons ± SEM in 6 stereotactic levels in the traumatized right side ofrats treated with either vehicle or the test compound of Example 3 weremeasured and the results listed in table 7 below. TABLE 7 Neuronaldensities CA3 hippocampus, cells × 10³/mm³ Compound of Compound ofCompound of Stereo- Vehicle right; Ex. 3, 2 hrs; Ex. 3, 4 hrs; Ex. 3, 8hrs; tactic level (n = 8) (n = 8) (n = 8) (n = 8) 10.21 55.21 ± 5.8172.30 ± 4.80 72.20 ± 5.70 62.00 ± 4.90 10.41 50.65 ± 7.30 68.10 ± 6.3065.90 ± 8.80 53.00 ± 6.44 10.61 49.35 ± 8.76 60.80 ± 5.60 63.00 ± 6.3053.00 ± 6.00 10.81 51.21 ± 7.97 60.20 ± 9.40  60.50 ± 10.50 52.50 ± 4.4811.01  54.80 ± 10.30  63.00 ± 11.70  62.20 ± 13.50 61.80 ± 4.48 11.21 60.00 ± 13.00  67.70 ± 14.00  66.30 ± 15.90 65.90 ± 4.90

Injection of vehicle resulted in decrease of neuronal densities in theCA3 hippocampus up to 35% of control values. Intracerebroventricularinjection of 10 μg of the test substance of Example 3 partiallyprevented hippocampal neuronal loss. ANOVA revealed that there was asignificant effect of treatment with of the test substance of Example 3on neuronal loss in the CA3 hippocampus for all three time points(P<0.001 at 2 and 4 hrs, P<0.01 for 8 hrs).

2. Adriamycin Toxicity: Determination of Anti-Apoptotic Activity

Wistar rats, weighing 200-250 g, were anesthetized with chloral hydrate,400 mg/kg, and Alzet osmotic minipumps (2ML1), were implantedsubcutaneously (=s.c.). The pumps had been filled with either vehicle orsolution containing compounds of the invention at the appropriateconcentration and primed prior to implantation. Animals subsequentlyreceived adriamycin at three equal daily doses of 5 mg/kg i.p. on days1, 2 and 3. Rats were euthanized 5 days after the first injection ofadriamycin and transcardially perfused with a solution containing 4%paraformaldehyde in phosphate buffer. The heart, liver and kidneys weresubsequently removed and embedded in parafin.

TUNEL staining: For terminal deoxynucleotide transferase-mediated dUTPnick end-label (TUNEL) based histological analysis, organs werepost-fixed for 5 days at 4° C. and paraffin-embedded. TUNEL staining wasperformed on 10 μm thick paraffin sections using the ApopTag Peroxidasekit (S 7100, Oncor Appligene, Heidelberg, Germany) according to themanufacturer's instructions. Briefly, after pretreatment with proteinaseK and quenching of endogenous peroxidase, sections were incubated inequilibration buffer followed by working strength TdT enzyme(incorporating digoxigenin labeled dUTP nucleotides to free 3′-OH DNAtermini), (1 hr, 37° C.). Sections were incubated in stop/wash buffer(30 min, 37° C.), then with anti-digoxigenin-peroxidase conjugate (30min) followed by DAB substrate (Sigma, Deisenhofen, Germany) and lightlycounterstained with methylgreen.

In this test model the test substance of Example 4 conferred significantprotection against adriamycin toxicity in the heart, liver and kidney inthat it significantly reduced the densities of TUNEL positive cells inthe three organs. This effect was dose-dependent with the dose of 100mg/kg and day being the most effective:

Wistar rats were administered adriamycin at the cumulative dose of 15mg/kg i.p. The test substance of Example 4 was administered s.c. at thedoses of 20, 50 or 100 mg/kg and day by means of Alzet osmotic minipumpsover 5 days. Animals were euthanized and transcardially perfused 5 daysafter the first injection of adriamycin and the heart, kidney and liverwere processed for TUNEL staining. Densities of TUNEL positive cellswere determined as described in the methods. Results for each organ(heart, liver, kidney) were measured as mean densities of TUNEL positivecells ±SEM for the control groups and the different test groups (20, 50or 100 mg/kg and day of test compound of Example 4) and listed in table8 below. TABLE 8 TUNEL positive cells/mm³ × 10² Heart Liver KidneyAdriamycin (n = 24) 5.417 ± 0.146   10.420 ± 0.275   9.438 ± 0.198   +Compound of Ex. 4; 4.350 ± 0.248*** 8.750 ± 0.301**  7.900 ± 0.306*** 20mg/kg (n = 10) + Compound of Ex. 4; 3.700 ± 0.260*** 8.250 ± 0.271***7.850 ± 0.587**  50 mg/kg (n = 10) + Compound of Ex. 4; 3.550 ± 0.157***7.450 ± 0.329*** 6.300 ± 0.260*** 100 mg/kg (n = 10)

The test substance of Example 4 dose-dependently decreased the cytotoxiceffect of adriamycin in all three organs. Comparisons between groupswere performed by means of Student's t test (**P<0.01; ***P<0.001compared to vehicle treated rats).

The present invention also provides a method of treating or preventingcardiovascular disorders or diseases and/or treatment of adverseconditions associated with apoptosis in mammals and humans comprisingadministering to a subject in need thereof an effective amount of acompound of Formula I.

The present invention further provides a method of treating orpreventing sexual dysfunction in mammals and humans comprisingadministering to a subject in need thereof an effective amount of adually acting compound capable of inhibiting NEP and hSEP, in particularof a compound of Formula I, according to the invention.

The compounds of Formula I may be administered in conventionalpharmaceutical compositions. The doses to be used may vary individuallyand will naturally vary according to the type of condition to be treatedand the substance used. In general, however, medicinal forms with anactive substance content of 0.2 to 500 mg, in particular 10 to 200 mg,active substance per individual dose are suitable for administration tohumans and larger mammals. The agents of the present invention may alsobe administered by intravenous infusion, at a dose which is likely torange from 0.001-10 mg/kg/hr. The above dosages are exemplary of theaverage case. The compounds may be contained according to the invention,together with conventional pharmaceutical auxiliaries and/or excipients,in solid or liquid pharmaceutical compositions. Examples of solidpharmaceutical compositions are compositions which can be administeredorally, such as tablets, coated tablets, capsules, powders or granules,or alternatively suppositories. These pharmaceutical compositions maycontain conventional pharmaceutical inorganic and/or organic excipients,such as talcum, lactose or starch, in addition to conventionalpharmaceutical auxiliaries, for example lubricants or tabletdisintegrating agents. Liquid pharmaceutical compositions such assuspensions or emulsions of the active substances may contain the usualdiluents such as water, oils and/or suspension agents such aspolyethylene glycols and the like. Other auxiliaries may additionally beadded, such as preservatives, taste correctives and the like.

The active substances may be mixed and formulated with thepharmaceutical auxiliaries and/or excipients in known manner. For thepreparation of solid medicament forms, the active substances may forexample be mixed with the auxiliaries and/or excipients in conventionalmanner and may be wet or dry granulated. The granules or powder may bepoured directly into capsules or be pressed into tablet cores inconventional manner. These may be coated in known manner if desired.

The following examples are intended to explain the invention further,without limiting its scope.

The mass spectra were measured using the following method:

-   HPLC-MS: API100 Quadrupol mass spectrometer (PE Applied Biosystems)    coupled to a LC200 pump (PE). Electrospray ionisation, positive    mode. Scan range m/z 100 to 1000. Software MassChrom 1.2. Xterra®    column (4.6 mm×50 mm, 2.5 μm).-   Solvent system: Water (10 mM ammonium acetate, pH 5) and    acetonitrile, linear gradient from 5% acetonitrile to 95% in 10 min.

EXAMPLE 1 Ethyl 2-{[(3S)-1-({[1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-(isopropylamino)-4-oxobutyrate

-   A) 91.9 ml benzyl alcohol was added to 99.07 g itaconic acid    anhydride and the mixture was stirred for 8 hours (=h) at 65° C. The    crystals produced on cooling were made into a slurry with 35 ml of a    mixture of n-hexane/diethyl ether 2:1 (v/v) and filtered off from    the solvent. The resulting crude product was dissolved in 150 ml    diethyl ether in warm conditions and crystallised again by addition    of 80 ml n-hexane. The combined mother lyes were reduced,    recrystallised corresponding to the above method and the crystals    obtained were finally added to the main quantity. 120 g    2-[(2-benzyloxy)-2-oxoethyl]acrylic acid was obtained which was used    directly for the next reaction without further purification, ¹H-NMR    (CDCl₃): 7.35, m, [5]; 6.47, s, [1]; 5.83, s, [1]; 5.15, s, [2];    3.40, s, [2] ppm.-   B) 100 g of the 2-[(2-benzyloxy)-2-oxoethyl]acrylic acid obtained    above was suspended in 100 ml methyl-tert. butylether (=MTBE) and    0.5 ml pyridine was added thereto. 47 ml thionyl chloride was added    dropwise thereto and the resulting mixture was heated for 1.5 hours    under reflux cooling to boiling. After cooling to room temperature,    it was evaporated approximately to dryness at reduced pressure. The    resulting residue was dissolved in 50 ml dichloromethane and added    dropwise at 0-5° C. to a receiving solution consisting of 16 ml    ethanol and 36.5 ml triethylamine in 150 ml dichloromethane. Once    addition had ended, stirring was continued for 1 hour at approx.    0° C. Then it was washed in succession twice with 250 ml water each    time, once with 100 ml dilute aqueous sodium bicarbonate solution    and finally once with saturated aqueous common salt solution. The    organic phase was dried over sodium sulfate and evaporated as far as    possible under reduced pressure. Distillation of the resulting    residue at 0.015 mbar and 150° C. yielded 56.3 g 2-methylenesuccinic    acid-4-benzylester-1-ethylester, which was used without further    purification or characterisation directly for the next reaction.-   C) 118 ml diisopropylamine was dissolved in 3 l dry tetrahydrofuran    (=THF) under nitrogen atmosphere and the solution was cooled to    0° C. 340 ml of a 2.5 M solution of n-butyllithium in n-hexane was    added to this receiving solution and stirring was continued for    another 45 minutes at 0° C. once the addition had ended. Then a    solution of 45 g cyclopentanecarboxylic acid in 100 ml dry THF was    dropped into the resulting mixture at 0-5° C. and the mixture was    then stirred for 2 hours at 0° C. It was cooled to −80° C. and a    solution of 72.6 g of a 2-methylenesuccinic    acid-4-benzylester-1-ethylester as obtained above (total quantity    from several batches) in 100 ml THF was added dropwise thereto. It    was stirred for 2 hours at −75° C. and then 1.5 l of a 2N aqueous    hydrochloric acid was added. After thawing and phase separation, the    aqueous phase was extracted twice with ethyl acetate (=EA), the    organic phases were combined and dried over sodium sulfate. The    solvent was evaporated at reduced pressure and volatile substances    were separated off by distillation at 0.02 mbar and 140° C.    Chromatography of the residue remaining after distillation on silica    gel (mobile phase: EA/n-hexane 1:6 to 1:7 v/v) yielded 22.8 g    1-[4-(benzyloxy)-2-(ethoxycarbonyl)-4-oxobutyl]cyclopentanecarboxylic    acid; ¹H-NMR (CDCl₃): 7.33, m, [5]; 5.10, s, [2]; 4.04, m, [2];    2.88, m, [1]; 2.80-2.48, AB-Q., [2]; 2.2-2.1, m, [2]; 1.7-1.4, m,    [6]; 1.20, tr, [3].-   D) 49.5 g of a    1-[4-(benzyloxy)-2-(ethoxycarbonyl)-4-oxobutyl]cyclopentanecarboxylic    acid as obtained above (total quantity from several batches) was    dissolved in 435 ml dichloromethane. 39.5 g tert.    butyl-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro)-1H-benzazepin-1-yl]acetate    (for production see EP 0 733 642 A1), 18.3 g hydroxybenzotriazole    and 60 ml morpholine were added to this receiving solution. Then 52    g EDCxHCl was added to the resulting mixture in one portion and    stirring was carried out overnight at room temperature. Then the    solvent was evaporated at reduced pressure and the remaining residue    was taken up in 750 ml of EA. The organic phase was washed in    succession twice with 100 ml 2N aqueous hydrochloric acid each time,    twice with 100 ml water each time and once with 100 ml saturated    aqueous common salt solution and dried over sodium sulfate.    Evaporation of the solvent at reduced pressure and drying of the    remaining residue in an oil pump vacuum (5×10⁻² mbar) yielded 87.9 g    2-{[(3S)-1-({[1-(2-tert.    butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}succinic    acid-4-benzylester-1-ethylester as yellowish oil, which was used    without further purification or characterisation for the subsequent    reaction.-   E) 87.9 g of the 2-{[(3S)-1-({[1-(2-tert.    butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}succinic    acid-4-benzylester-1-ethylester obtained above was dissolved in 600    ml ethylacetate (=EA) and 20 g palladium on activated carbon (=Pd/C)    was added thereto. It was hydrogenated for 2 hours at a hydrogen    pressure of 1 bar and the reaction mixture was then filtered over    Cellite. The filter cake was subsequently washed with 1.5 l EA and    the combined organic phases were very largely evaporated at reduced    pressure. The residue was taken up in 500 ml EA/cyclohexane (1:1,    v/v) and extracted twice with 200 ml semi-saturated Na₂CO₃ solution    each time. The aqueous phase was acidulated with conc. KHSO₄    solution and extracted 3 times with 200 ml EA each time. After    drying over sodium sulfate, it was evaporated under reduced    pressure. Drying of the remaining residue in an oil pump vacuum    yielded 71 g 3-{[1-({[(3S)-1-(2-tert.    butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-methoxy-4-oxobutyric    acid as white foam, ¹H-NMR (CDCl₃): 7.31-7.17, m, [3]; 7.11, d,    [0.5]; 7.08, d, [0.5]; 6.81, d, [0.5]; 6.73, d, [0.5].

The intermediate product obtained in this case can if desired beseparated into its diastereomerically pure constituents by preparativehigh-performance liquid chromatography (=HPLC). 70 g of the intermediateproduct obtained above was separated off using the method set forthbelow:

Column: LC80-1, 23.4×8 cm; stationary phase: 740 g ChiralpakAD, 20 p;mobile phase: heptane/isopropanol (85:15); UV detection; cycle time: 45minutes;

Analysis: stationary phase: Chiralpak AD, 20 p; mobile phase:heptane/isopropanol 9:1 (v/v), flow rate: 2 ml/min; cycle time: 15minutes.

With a retention time of 11.6 min., there was obtained 30 g of the firststereoisomer, which was assigned the designation “rel1” in relation tothe chiral center “*C_(a)” bearing the group —COOR¹, as(3“rel1”)-3-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-ethoxy-4-oxobutyricacid, ¹H-NMR (CDCl₃): 7.31-7.18, m, [3]; 7.09, d, [1]; 6.74, d, [1];4.53, 4.48, 4.37, 4.32, AB-Q., [2]; 4.48, m, [1]; 4.11, m, [1].

With a retention time of 6.5 min., there was obtained 33 g of the secondstereoisomer, which was assigned the designation “rel2” in relation tothe chiral center “*C_(a)” bearing the group “—COOR¹”, as(3“rel2”)-3-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]ethyl}4-ethoxy-4-oxobutyricacid, ¹H-NMR (CDCl₃): 7.31-7.17, m, [3]; 7.11, d, [2]; 6.81, d, [1];4.60, 4.56, 4.35, 4.31, AB-Q. [2]; 4.48, m, [1]; 4.10, m, [1];[a]D=−136° (1% in methanol).

-   F) 4 g of the 3-{[1-({[(3S)-1-(2-tert.    butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-ethoxy-4-oxobutyric    acid obtained above was dissolved in 15 ml dichloromethane. After    this receiving solution had been cooled to 0° C., 1.12 ml    triethylamine and 0.77 ml ethyl chloroformate were added slowly    dropwise thereto in succession and the mixture was stirred for 30    minutes at 0° C. Then 0.94 ml of isopropylamine was added thereto    and stirring was continued for a further 3 hours at 0° C. The    solvent was largely evaporated at reduced pressure and the remaining    residue was taken up in 100 ml EA. The organic phase was washed in    succession once each with 50 ml saturated aqueous KHSO₄ solution and    with saturated aqueous common salt solution, dried over sodium    sulfate and the solvent was very largely evaporated at reduced    pressure. Drying of the remaining residue in an oil pump vacuum    yielded 4.29 g of the title compound as yellowish oil, MS: [M+H]⁺:    586; m/z: 530; 484; 425.

EXAMPLE 22-{[(3S)-1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-(isopropylamino)-4-oxobutyricAcid

9.97 g of an ethyl 2-{[(3S)-1-({[1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-(isopropylamino)-4-oxobutyrateas obtained above under 1 E) was dissolved in 200 ml of a water/ethanolmixture (1:1 v/v) and 6.64 g solid NaOH was added thereto with stirring.Stirring was continued over night, the solvent was then very largelyevaporated at reduced pressure and the remaining residue was taken up in100 ml of EA. The aqueous phase was neutralised with saturated aqueousKHSO₄ solution and extracted three times with EA. The combined organicphases were washed with 100 ml saturated aqueous common salt solutionand dried over sodium sulfate. Evaporation of the solvent at reducedpressure and drying of the remaining residue in an oil pump vacuumyielded 5.59 g of the title compound.

EXAMPLE 3(2“rel1”)-2-{[(3S)-1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-(isopropylamino)-4-oxobutyricAcid

400 mg of the diastereomer mixture obtained above in Example 2) wasseparated by HPLC in accordance with the procedure set forth below:

Column: LC80-1, 25×8 cm; stationary phase: ChiralpakAD, 20μ; mobilephase: heptane/isopropanol 85:15 (v/v)+0.1% v/v trifluoroacetic acid(=TFA); UV detection; flow rate: 1 ml/min.; cycle time: 15 minutes;

Analysis: column: DAICEL Chiralpak AD; length: 250 mm; diameter: 4.6 mm;mobile phase: n-heptane 800 ml, 2-propanol 200 ml, TFA 2 ml; flow rate:0.8 ml/min.; analysis time: 30 minutes. With a retention time of 13.5min., there was obtained under these conditions 130 mg of the firststereoisomer (=title compound), which was assigned the designation“rel1” in relation to the chiral center “*C_(a)” bearing the group“—COOR¹”, as white solid, which precipitated from EE; ¹H-NMR (methanol):7.37-7.2, m, [4]; 4.76, 4.71, 4.43, 4.38, AB-Q.; 4.4, m, [1]; 3.90, m,[1]; 3.40, m, [1]; 2.22-2.60, m, [2]; 2.48-2.0, m, [12]; 1.10, d, [6];[a]D=−90° (0.5% in methanol); Mp.: 145° C. With a retention time of 16.2min., there was obtained under these conditions the second stereoisomer,which was assigned the designation “rel2” in relation to the chiralcenter “*C_(a)” bearing the group “—COOR¹”.

EXAMPLE 4{(3S)-3-[({1-[(2“rel1”)-2-ethoxycarbonyl)-4-(isopropylamino)-4-oxobutyl]cyclopentyl}-carbonyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl}aceticAcid

4.29 g ethyl (2“rel1”)-2-{[(3S)-1-({[1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-(isopropylamino)-4-oxo-butyrate(prepared analogously to Example 1, but with the(3“rel1”)-3-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-ethoxy-4-oxobutyricacid obtained by HPLC separation being used as intermediate product ofstage 1 E), was dissolved in 30 ml dichloromethane and 17 ml of TFA wasadded. The mixture was left to stand overnight and the solvent andexcess TFA were evaporated at reduced pressure. The remaining residuewas taken up in 100 ml EA and the organic phase was washed with wateruntil it became pH-neutral. The organic phase was dried over sodiumsulfate and then the solvent was very largely evaporated at reducedpressure. 30 ml toluene in each case was added twice to the residue andthe mixture was again evaporated at reduced pressure. Drying of theremaining residue in an oil pump vacuum yielded 2.8 g of the titlecompound as white foam; ¹H-NMR (CDCl₃): 7.33, m, [4]; 6.82, d, [1];5.86, d, [1]; 4.64, m, [1]; 4.54, 4.50, 4.46, 4.42, AB-Q.; 3.20, m, [1];1.23, [3]; 1.09, [6]; [a]D: −155° (1% in methanol).

EXAMPLE 5 Ethyl (2“rel1”)-2-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-[(3-hydroxypropyl)amino]-4-oxobutyrate

4.2 g (3“rel1”)-3-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-ethoxy-4-oxobutyricacid (preparation of the diastereomer mixture in accordance with Example1E) and subsequent separation of the diastereomers by means of HPLC) wasdissolved in 30 ml dichloromethane. 1.17 ml 3-amino-1-propanol, 235 mgdimethylaminopyridine and 1.61 g EDC were added to this receivingsolution with stirring. After 1 h, the mixture was largely evaporated atreduced pressure, the remaining residue was taken up in 100 ml EA andthe organic phase was shaken out twice with 30 ml dilute aqueous KHSO₄solution each time. The organic phase was washed twice more with 30 mlsaturated aqueous common salt solution each time, dried over sodiumsulfate and the solvent was then largely evaporated at reduced pressure.Drying of the remaining residue in an oil pump vacuum yielded 4 g of thetitle compound as white foam resin, MS: [M+H]⁺: 602; m/z: 546, 500, 425;¹H-NMR (CDCl₃): 7.32-7.18, m, [3]; 7.12, d, [2]; 6.63, d, [1]; 6.49, tr,[1]; 4.57, 4.63, 4.34, 4.30, AB-Q. [2]; 4.51, m, [1]; 4.11, m, [2];3.57, tr, [2].

EXAMPLE 6 Ethyl(2“rel1”)-4-{[3-(acetyloxy)propyl]amino}-2-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-oxobutyrate

1 g of the ethyl (2“rel1”)-2-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino]}carbonyl)cyclopentyl]methyl}-4-[(3-hydroxypropyl)-amino-4-oxobutyrateobtained above in Example 5 was dissolved in 20 ml dichloromethane and340 μl acetyl chloride was added thereto. After 90 minutes, the solventwas largely evaporated at reduced pressure and the remaining residue wastaken up in 20 ml EA and washed with 10 ml of a dilute aqueous sodiumbicarbonate solution. Then it was dried over magnesium sulfate, thesolvent was largely evaporated at reduced pressure and the remainingresidue was chromatographed on silica gel (mobile phase: EA/n-hexane 7:3v/v). Drying the product fractions in an oil pump vacuum (5×10⁻² mbar)yielded 920 g of the title compound as colourless oil; MS: [M+H]: 644;m/z: 588, 542, 482, 425.

EXAMPLE 7{(3“rel1”)-3-[({1-[(2S)-4-{[3-(acetyloxy)propyl]amino}-2-(ethoxycarbonyl)-4-oxobutyl]cyclopentyl}carbonyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl}aceticAcid

929 mg of the ethyl(2“rel1”)-4-{[3-(acetyloxy)propyl]amino}-2-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)-cyclopentyl]methyl}-4-oxobutyrateobtained above in Example 6 was dissolved in 10 ml dichloromethane and2.2 ml TFA was added thereto. The mixture was left to stand overnight,the solvent was then largely evaporated at reduced pressure and theremaining residue was taken up in 30 ml EA. The organic phase was washedwith water until it became pH neutral, was again largely evaporated atreduced pressure and the remaining residue was fumed off twice with 10ml toluene each time. 750 mg of the title compound was obtained as awhite foam resin, MS: [M+H]: 588; m/z: 542, 482, 425; ¹H-NMR (CDCl₃):7.33-7.14, m, [4]; 6.67, d, [1]; 6.59, tr, [1]; 4.69, 4.64, 4.35, 4.30,AB-Q., [2]; 4.63, m, [1]; 4.17, m, [1]; 4.09, q, [2]; 3.33, m, [1];3.15, m, [2].

EXAMPLE 8((3S)-3-{[(1-{(2“rel1”)-2-ethoxycarbonyl)₄-[(3-hydroxypropyl)amino]-4-oxobutyl]cyclopentyl}-carbonyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl}aceticAcid

580 mg ethyl (2“rel1”)-2-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino]}carbonyl)cyclopentyl]methyl}-4-[(3-hydroxypropyl)amino-4-oxobutyrate(for preparation see Example 5) was reacted with TFA in accordance withthe method set forth above in Example 4. After purification of theresulting crude product by column chromatography (stationary phase:silica gel; mobile phase: EA/methanol 9:1 (v/v)), 240 mg of the titlecompound was obtained as colourless resin, ¹H-NMR (CDCl₃): 7.34-7.15, m,[4]; 6.76, tr, [1]; 6.61, d, [1]; 4.75, 4.71, 4.20, 4.16, AB-Q., [2];4.57, m, [1]; 4.09, q, [2]; MS: [M+H]⁺: 546; [a]D=−112.5° (1% inmethanol).

EXAMPLE 92-{[1-({[(3S)-1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-[(3-hydroxypropyl)amino]-4-oxobutyricAcid

6.43 g ethyl (2S)-2-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-[(3-hydroxypropyl)amino]-4-oxobutyrate(for preparation see Example 5) was dissolved in 140 ml of a 1:1 (v/v)mixture of water and ethanol, and 4.28 g solid NaOH was added theretowith stirring. After 15 h, the solvent was evaporated at reducedpressure, the residue was taken up in 100 ml EA and washed once with 50ml aqueous KHSO₄ solution. The aqueous phase was extracted twice with 30ml EA each time. The combined organic phases were washed twice with 30ml aqueous common salt solution each time and dried over sodium sulfate.Evaporation of the solvent yielded 5.41 g of the title compound.

EXAMPLE 10(2“rel1”)-2-{[1-({[(3S)-1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-[(3-hydroxypropyl)amino]-4-oxobutyricAcid

800 mg of the isomer mixture obtained above in Example 9 was separatedby preparative HPLC in accordance with the procedure set forth below:

-   Stationary phase: Nucleosil 100-10; column: 250 mm long, 20 mm    diameter; flow rate: 8 ml/min.; mobile phase: n-heptane (800 ml),    2-propanol (200 ml), TFA (1 ml).

Analysis: stationary phase: EC 250/4 Nucleosil 100-10; column 250 mllong, 4 mm diameter, flow rate: 1.5 ml/min.; mobile phase: n-heptane(800 ml), 2-propanol (200 ml), TFA (1 ml). With a retention time of 7.89min., there was obtained under these conditions 200 mg of the firststereoisomer (=title compound), which was assigned the designation“rel1” in relation to the chiral center “*Ca” bearing the group“—COOR¹”, ¹H-NMR (CD₃OD): 7.38, m, [4]; 4.78, 4.73, 4.43, 4.38, AB-Q.,[2]; 4.41, m, [1]; 3.93, m, [1]; 3.56, tr [2]; 3.40, m, [1]; 3.31, m,[1]; 3.22, m, [2]; 2.78, m, [1]; 2.65, m, [1].

With a retention time of 4.47 min., there was obtained under theseconditions the second stereoisomer, which was assigned the designation“rel2” in relation to the chiral center “*Ca” bearing the group“—COOR¹”.

EXAMPLE 112-{[1-({[(3S)-1-(2-ethoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-[(3-hydroxypropyl)amino]-4-oxobutyricAcid

800 mg of the2-{[1-({[(3S)-1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-[(3-hydroxypropyl)amino]-4-oxobutyricacid (isomer mixture) obtained above according to Example 9 wasdissolved in 15 ml dimethyl formamide (=DMF). 302.5 mg Cs₂CO₃ and 169 mgethyl bromide were added to this receiving solution at room temperaturewith stirring. After stirring overnight, it was diluted with 42 ml waterand 21 ml dichloromethane and the aqueous phase was extracted withdichloromethane. The solvent was largely evaporated at reduced pressureand the remaining residue was chromatographed (stationary phase: silicagel, mobile phase: EA (100%) to EE/MeOH 7:3 (v/v)). Drying the productfractions in an oil pump vacuum (5×10⁻² mbar) yielded 241 g of the titlecompound as foam resin, MS: [M+H]⁺: 546; m/z: 453, 425, 379; ¹H-NMR(CDCl₃): 7.34-7.1, m, [4]; 4.82, 4.77, 4.34, 4.29, AB-Q-. [2]; 3.62, m,[2]; 3.37, m, [3].

EXAMPLE 12 2-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-(isopropylamino)-4-oxobutyricAcid

2.6 g ethyl 2-{[(3S)-1-({[1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-(isopropylamino)-4-oxobutyrate(for preparation see Example 1) was dissolved in 52 ml of ethanol. Asolution of 710 mg solid NaOH in 52 ml water was added to this receivingsolution. After 30 minutes, it was acidulated with dilute aqueous KHSO₄solution to approximately pH 2 and the aqueous phase was extracted threetimes with 50 ml EA each time. The combined organic phases were driedover magnesium sulfate, the solvent was largely evaporated at reducedpressure and the remaining residue was chromatographed on silica gel(mobile phase: EA/cyclohexane 2:1 v/v). Drying the product fractions inan oil pump vacuum (5×10⁻² mbar) yielded 2.2 g of the title compound aswhite foam resin, MS: [M+H]⁺: 558; m/z: 502, 425, 397, 323.

EXAMPLE 13 4-chlorobenzyl-2-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-(isopropylamino)₄-oxobutyrate

300 mg of the 2-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-(isopropylamino)₄-oxobutyricacid obtained above was dissolved in 5 ml dichloromethane. 33 mg of4-dimethylaminopyridine (=DMAP), 85 mg 4-chlorobenzyl alcohol and 124 mgEDCxHCl were added thereto and stirring was then carried out overnight.The mixture was diluted with 5 ml dichloromethane and the organic phasewas washed in succession once each with 2 ml dilute aqueous KHSO₄solution and with saturated aqueous common salt solution. The organicphase was dried over magnesium sulfate, the solvent was largelyevaporated to dryness at reduced pressure and the remaining residue waschromatographed on silica gel (mobile phase: EA/cyclohexane 3:2 v/v).Drying the product fractions in an oil pump vacuum (5×10⁻² mbar) yielded320 g of the title compound as white foam; MS: [M+H]⁺: 682/684; m/z:626/628, 576, 484, 425.

EXAMPLE 14{(3S)-3-[({1-[2-{[(4-chlorobenzyl)oxy]carbonyl}-4-(isopropylamino)-4-oxobutyl]cyclopentyl}carbonyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl}aceticAcid

318 g of the 4-chlorobenzyl-2-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-(isopropylamino)-4-oxobutyrateobtained above was dissolved in 11 ml dichloromethane, 1.08 ml TFA wasadded thereto and the mixture was stirred overnight. Then the solventwas largely evaporated at reduced pressure, the remaining residue wastaken up in 10 ml EA and the organic phase was washed with water untilit became pH-neutral. Then the solvent was evaporated again at reducedpressure and the remaining residue was fumed off once with 5 ml oftoluene. 305 mg of the title compound was obtained as a white foamresin, MS: [M+H]⁺: 626/628; m/z: 657, 484, 425.

EXAMPLE 15 (2-methoxyethoxy)methyl-2-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-(isopropylamino)-4-oxobutyricAcid

300 mg 2-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-(isopropylamino)-4-oxobutyricacid (for preparation see Example 12) was dissolved in 5 mldichloromethane. 33 mg DMAP, 74 μl methoxyethoxymethyl chloride and 90μl triethylamine were added to this receiving solution. The reactionmixture was stirred overnight, then diluted with 5 ml dichloromethaneand the organic phase was washed in succession once each with 3 mldilute aqueous KHSO₄ solution and saturated aqueous common saltsolution. The organic phase was dried over magnesium sulfate, thesolvent was largely evaporated at reduced pressure and the remainingresidue was chromatographed on silica gel (mobile phase: EA/cyclohexane2:1 v/v). Drying the product fractions in an oil pump vacuum yielded 191g of the title compound, MS: [M+H]⁺: 646; m/z: 590, 540, 484, 425.

EXAMPLE 44 Ethyl(2“rel1”)-2-{[1-({[(3S)-1-(2-ethoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-[(3-hydroxypropyl)amino]-4-oxobutyrate

140 mg{(3S)-3-[({1-[(2“rel1”)-2-ethoxycarbonyl)-4-(isopropylamino)₄-oxobutyl]cyclopentyl}-carbonyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl}aceticacid (for preparation see Example 4) was dissolved in 3 ml ethanol, 5drops of conc. sulfuric acid were added thereto and the mixture wasstirred for 2 days at room temperature. Then the solvent was largelyremoved at reduced pressure and the remaining residue was taken up in 5ml EA. The organic phase was washed twice with 2 ml aqueous NaHSO₄solution each time. After drying over sodium sulfate, the solvent wasdistilled off at reduced pressure and the residue was chromatographed onsilica gel (mobile phase: EA/cyclohexane 8:2 (v/v)). 46 mg of the titlecompound was obtained as a white foam; MS: [M+H]⁺: 574; m/z: 528, 323;¹H-NMR (CDCl₃): 7.33-7.11, m, [4]; 6.69, m, [1]; 6.44, m, [1]; 4.79,4.75, 4.34, 4.30, AB-Q-. [2]; 4.48, m, [1].

The compounds of Formula I listed in the following Table 9 can also beprepared according to the processes described in the examples above orin a manner analogous to said processes. TABLE 9 Further compounds ofFormula I Ex. Config. Config. No. R¹ R² R³ R⁴ C_(a)* C_(b)* [M + H]⁺ 16H H methoxyethyl H rac S 518 17 H H 3-(2-oxoazepanyl) H rac S 571 18ethyl —(CH₂)₂—O—(CH₂)₂— H rac S 558 19 H —(CH₂)₂—O—(CH₂)₂— H rel1 S 20 HH 4-methoxyphenyl- H rac S 608 2-oxoethyl 21 H H 3-oxo-1,1- H rac S 558dimethylbutyl 22 H H phenyl-2-oxoethyl H rac S 578 23 H Hcyclopropylmethyl H rac S 514 24 H H 4-methoxybenzyl H rac S 580 25 H H4-methoxyphenyl- H rac S 594 ethyl 26 H H 2-methoxybenzyl H rac S 580 27H H benzyl H rac S 550 28 H H methyl H rac S 474 29 ethyl H2-(4-methoxy- H rac S 636 phenyl)-2-oxoethyl 30 ethyl H methoxyethyl Hrel1 S 546 31 H H 2-methoxybenzyl H rac S 580 32 H methyl isopropyl Hrac S 516 33 ethyl H 3,4-dimethoxy- H rac S 638 benzyl 34 ethyl Hcyclopropyl H rac S 528 35 Et H 2-hydroxyethyl H rac S 532 36 Et H4-methoxybenzyl H rac S 608 37 Et H 1-naphthylmethyl H rac S 628 38 Et H4-methoxyphenyl- H rac S 622 ethyl 39 isopropyl H isopropyl H rac S 54440 n-butyl H isopropyl H rac S 558 41 H H isopropyl methoxy- rac S 590ethoxy- methyl 42 2-chloro- H isopropyl H rac S 627 benzyl 43 H methyl2-hydroxyethyl H rac S 518 44 see above 45 H —(CH₂)₂—CO—(CH₂)₂— H rac S542 46 Et —(CH₂)₂—CO—(CH₂)₂— H rac S 570 47 Et —(CH₂)₂—N(Bn)—(CH₂)₂— Hrac S 647 48 Et —(CH₂)₂—S—(CH₂)₂— H rac S 574 49 H —(CH₂)₄— H rac S 51450 H —(CH₂)₃—CH(CH₂—OH)—CH₂— H rac S 558 51 H methyl —CH₂—(CHOH)— H racS 548 CH₂OH 52 H ethyl —(CH₂)₃—NH—C₂H₅ H rac S 573 53 Et 2-hydroxy-2-hydroxyethyl H rac S 576 ethyl 54 H methyl methyl H rac S 488 55 Hethyl ethyl H rac S 516 56 H methyl 3-hydroxypropyl H rac S 532 57 H—(CH₂)₂—CH(OH)—(CH₂)₂— H rac S 544 58 H 2-hydroxy- 2-hydroxyethyl H racS 548 ethyl 59 H methyl —(CH₂)₂—N(CH₃)₂ H rel1 S 545 60 H methyl—(CH₂)₃—N(CH₃)₂ H rac S 559 61 Et —(CH₂)₂—CH(—O-valine)-(CH₂)₂— H rac S671 62 Et methyl —(CH₂)₃—O-valine H rac S 659 63 H methyl isopropyl Hrel1 S 516 64 H methyl —(CH₂)₃—N(CH₃)₂ H rel1 S 559 65 H methyl—(CH₂)₃—NH₂ H rac S 531 66 H —(CH₂)—O—(CH₂)₂ H rac S 530 67 H ethyl—(CH₂)₃—NH₂ H rac S 545 68 H methyl —(CH₂)₂—NH(CH₃) H rac S 531 75 Hmethyl —(CH₂)₄—NH₂ H rac S 545 76 H ethyl —(CH₂)₄—NH₂ H rac S 559 77 Hmethyl —(CH₂)₃—NH(CH₃) H rac S 545 78 H Methyl —(CH₂)₅—NH₂ H rac S 79 Hethyl —(CH₂)₅—NH₂ H rac Srac = racemic;Bn = benzyl

EXAMPLE 69 Tert. butyl 2-{[1-({[(3S)-1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-(4-hydroxypiperidin-1-yl)-4-oxobutanoate

-   A) 100 g of 2-[(2-benzyloxy)-2-oxoethyl]acrylic acid (for production    see example 1A) was reacted with 47 ml of thionyl chloride, 43 ml of    tert. butanol and 110 ml of pyridine according to the procedure    described in example 1B) to yield 69.8 g of 2-methylenesuccinic    acid-4-benzylester-1-tert. butylester, [M+H]⁺: 277.-   B) 29.6 g of 2-methylenesuccinic acid-4-benzylester-1-tert.    butylester as obtained above was reacted with 41.4 ml of    diisopropylamine, 200 ml of a 1.6 M solution of n-butyllithium in    n-hexane and 12 ml of cyclopentanecarboxylic acid according to the    procedure described in example 1C) to yield 24.5 g of    1-[4-(benzyloxy)-2-(tert.    butoxycarbonyl)-4-oxobutyl]cyclopentanecarboxylic acid.-   C) 15.8 g of 1-[4-(benzyloxy)-2-(tert.    butoxycarbonyl)-4-oxobutyl]cyclopentane-carboxylic acid as obtained    above was reacted with 11.75 g of tert.    butyl-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro)-1H-benzazepin-1-yl]acetate    (for production see EP 0 733 642 A1) according to the procedure    described in example 1D) to yield 21 g of 2-{[(3S)-1-({[1-(2-tert.    butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}succinic    acid-4-benzylester-1-tert. butylester.-   D) 21 g of 2-{[(3S)-1-({[1-(2-tert.    butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}succinic    acid-4-benzylester-1-tert. butylester as obtained above was treated    with 6 g of palladium on activated carbon and hydrated for 12 hours    and a hydrogen pressure of 1.3 bar according to the procedure    described in example 1E) to yield 10 g of 4-tert.    butoxy-3-{[1-({[(3S)-1-(2-tert.    butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-oxobutanoic    acid; MS: [M+H]⁺: 573; m/z: 517, 461; ¹H-NMR (CDCl₃): 7.31-7.17, m,    [3]; 7.10, m, [1]; 6.80, d, [0.5]; 6.72, d, [0.5]; 4.60-4.30, m,    [3]; 3.30, m, [0.5]; 3.17, m, [0.5].-   E) 1.11 g of 4-tert. butoxy-3-{[1-({[(3S)-1-(2-tert.    butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-oxobutanoic    acid as obtained above was dissolved in 7.8 ml of dichloromethane    and 300 μl of triethylamine was added. After cooling to 0° C. in an    ice bath, 222 μl of ethylchloroformate was added dropwise to this    receiving solution. The mixture was allowed to stir for 30 minutes,    then 216 mg of 4-hydroxypiperidine was added and the mixture was    stirred over night. The mixture was diluted with EA and washed with    aqueous KHSO₄— solution and with brine. Drying of the organic layer    over magnesium sulfate and column chromatography on silica gel    (liquid phase: EA/cyclohexane 1:1(v/v) changed to pure EA changed to    EA/methanol 4:1 (v/v)) yielded 550 mg of the title compound as a    white foam, MS: [M+H]⁺: 656; m/z: 425, 397, 323.

EXAMPLE 702-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-oxo-4-[4-(L-valyloxy)piperidin-1-yl]butanoicAcid

-   A) 548 mg of tert. butyl 2-{[1-({[(3S)-1-(2-tert.    butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-(4-hydroxy-piperidin-1-yl)-4-oxobutanoate    as obtained in example 67 was dissolved in 3 ml of dichloromethane.    Then 51 mg of DMAP, 182 mg of BOC-L-valine and 176 mg of EDC were    added. After stirring for 3 hours the mixture was diluted with EA    and consecutively washed with aqueous KHSO₄ solution and with brine.    Drying of the organic layer over magnesium sulfate and column    chromatography on silica gel (liquid phase: EA/cyclohexane 1:1 (v/v)    changed to pure EA) yielded 551 mg of 1-(4-tert.    butoxy-3-{[1-({[(3S)-1-(2-tert.    butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-oxobutanoyl)piperidin-4-yl-N-(tert.    butoxycarbonyl)-L-valinate, MS: [M+H]⁺: 855; m/z: 699, 643, 625,    425, 397, 323, 235.-   B) 551 mg of 1-(4-tert. butoxy-3-{[1-({[(3S)-1-(2-tert.    butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-oxobutanoyl)piperidin-4-yl-N-(tert.    butoxycarbonyl)-L-valinate as obtained above was dissolved in 14 ml    of dichloromethane and 1.49 ml of trifluoroacetic acid was added to    this receiving solution. After stirring over night the solvent and    excess of acid were evaporated at reduced pressure. EA was added to    the remaining residue and the organic layer was washed with an    aqueous saturated sodium bicarbonate solution until a pH of 4 was    reached. The aqueous layer was then extracted thrice with EA and the    combined organic layers were dried over magnesium sulfate.    Evaporation of the solvent at reduced pressure and subsequent drying    of the remaining residue in an oil pump vacuum yielded 310 mg of the    title compound as a white foam, MS: [M+H]: 643; m/z: 425, 397, 323.

EXAMPLE 71 Tert. butyl2-{[1-({[(3S)-1-(2-ethoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-[isopropyl(methyl)amino]-4-oxo-butanoate

-   A) 20 g of 1-[4-(benzyloxy)-2-(tert.    butoxycarbonyl)-4-oxobutyl]cyclopentanecarboxylic acid (for    preparation see example 69B)) was reacted with 13.4 g of    ethyl-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro)-1H-benzazepin-1-yl]acetate    (preparation analogous to methods described in EP 0 733 642 A1)    according to the procedure described in example 1D) to yield 28.6 g    of 4-benzyl-1-tert.    butyl-2-{[1-({[(3S)-1-(2-ethoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)-cyclopentyl]methyl}succinate.-   B) 28.6 g of 4-benzyl-1-tert.    butyl-2-{[1-({[(3S)-1-(2-ethoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}succinate    as obtained above was treated with 5 g of palladium on activated    carbon and hydrated for 4.5 hours and a hydrogen pressure of 2.3 bar    according to the procedure described in example 1E) to yield 16 g of    4-tert.    butoxy-3-{[1-({[(3S)-1-(2-ethoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-oxobutanoic    acid, [M+H]⁺: 545; m/z: 489.-   C) 3 g of 4-tert.    butoxy-3-{[1-({[(3S)-1-(2-ethoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-oxobutanoic    acid as obtained above was reacted with 859 μl methylisopropylamine    according to the procedure described in example 1F) to yield 1.6 g    of the title compound as a white foam, MS: [M+H]⁺: 600; m/z: 544.

EXAMPLE 722-{[1-({[(3S)-1-(2-Ethoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]-amino}carbonyl)cyclopentyl]methyl}4-[isopropyl(methyl)amino]-4-oxobutanoicAcid

507 mg of tert. butyl2-{[1-({[(3S)-1-(2-ethoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-[isopropyl(methyl)amino]-4-oxo-butanoateas obtained in example 69 was dissolved in 18 ml of dichloromethane and1.95 ml of trifluoroacetic acid was added to this receiving solution.After stirring over night the solvent and excess of acid were evaporatedat reduced pressure. EA was added to the remaining residue and theorganic layer was washed with an aqueous saturated sodium bicarbonatesolution, until the aqueous layer reached a pH of 5. The organic layerwas then dried over magnesium sulfate. Drying of the organic layer overmagnesium sulfate and column chromatography on silica gel (liquid phase:EA/cyclohexane 1:1 (v/v) changed to pure EA) yielded 430 mg of the titlecompound as a white foam, MS: [M+H]⁺: 544.

EXAMPLE 73 1-[(Ethoxycarbonyl)oxy]ethyl2-{[1-({[(3S)-1-(2-ethoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-[isopropyl(methyl)-amino]-4-oxobutanoate

107 mg of2-{[1-({[(3S)-1-(2-Ethoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-[isopropyl(methyl)amino]-4-oxobutanoicacid (for preparation see example 72) was dissolved in 1 ml of DMF. Then83 μl of triethylamine, 20 mg of solid K₂CO₃ and 85 μl ofchloroethylethylcarbonate was added. After stirring over night themixture was diluted with EA and consecutively washed with an aqueousKHSO₄ solution and with brine. Drying of the organic layer overmagnesium sulfate and column chromatography on silica gel (liquid phase:EA/cyclohexane 1:1 (v/v)) yielded 41 mg of the title compound as a whitefoam, MS: [M+H]⁺: 660; m/z: 526, 449, 310, 253.

EXAMPLE 74 1-[(Ethoxycarbonyl)oxy]ethyl2-{[1-({[(3S)-1-(2-{1-[(ethoxycarbonyl)oxy]ethoxy}-2-oxo-ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]-methyl}-4-[isopropyl(methyl)amino]-4-oxobutanoate

500 mg of ethyl2-{[1-({[(3S)-1-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-[isopropyl(methyl)amino]-4-oxo-butanoate(see example 32, synthesis analogous to example 2) was dissolved in 10ml of DMF. Then 312 μl of chloroethylethylcarbonate, 758 mg of solidCs₂CO₃ and 80 mg of solid potassium iodide were added. After stirringfor 5 hours at 60° C. the mixture was diluted with EA and was then twicewashed with water. Drying of the organic layer over magnesium sulfateand column chromatography on silica gel (liquid phase: cyclohexane,changed to EA/cyclohexane 1:1 (v/v)) yielded 360 mg of the titlecompound as a white oil, MS: [M+H]⁺: 748; m/z: 614, 480.

EXAMPLE I Capsules Containing {(3S)-3-[({1-[(2“rel1”)-2-ethoxycarbonyl)-4-(isopropylamino)-4-oxobutyl]cyclopentyl}-carbonyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl}aceticAcid

Capsules with the following composition per capsule were produced:{(3S)-3-[({1-[(2“rel1”)-2-ethoxycarbonyl)-4-(isopropyl-amino)-4-oxobutyl]cyclopentyl}-carbonyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl}-aceticacid 20 mg Corn starch 60 mg Lactose 300 mg EA q.s.

The active substance, the corn starch and the lactose were processedinto a homogeneous pasty mixture using EA. The paste was ground and theresulting granules were placed on a suitable tray and dried at 45° C. inorder to remove the solvent. The dried granules were passed through acrusher and mixed in a mixer with the further following auxiliaries:Talcum 5 mg Magnesium stearate 5 mg Corn starch 9 mgand then filled into 400 mg capsules (=capsule size 0).

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

1. A compound corresponding to the formula I:

wherein R¹ is hydrogen or a group forming a biolabile ester, R² ishydrogen, C₁₋₄-alkyl or C₁₋₄-hydroxyalkyl, the hydroxyl group of whichis optionally esterified with C₂₋₄-alkanoyl or an amino acid residue,and R³ is C₁₋₄-alkyl; C₁₋₄-alkoxy-C₁₋₄-alkyl; C₁₋₄-hydroxyalkyl, whichis optionally substituted by a second hydroxyl group and the hydroxylgroups of which are each optionally esterified with C₂₋₄-alkanoyl or anamino acid residue; (C₀₋₄-alkyl)₂amino-C₁₋₆-alkyl; C₃₋₇-cycloalkyl;C₃₋₇-cycloalkyl-C₁₋₄-alkyl; phenyl-C₁₋₄-alkyl, the phenyl group of whichis optionally substituted once or twice by C₁₋₄-alkyl, C₁₋₄-alkoxy orhalogen; naphthyl-C₁₋₄-alkyl; C₃₋₆-oxoalkyl; phenylcarbonylmethyl, thephenyl group of which is optionally substituted once or twice byC₁₋₄-alkyl, C₁₋₄-alkoxy or halogen, or 2-oxoazepanyl, or R² and R³together are C₄₋₇-alkylene, the methylene groups of which are optionallyreplaced once or twice by carbonyl, nitrogen, oxygen or sulphur, orwhich are optionally substituted once by hydroxy, which is optionallyesterified with C₂₋₄-alkanoyl or an amino acid residue; C₁₋₄-alkyl;C₁₋₄-hydroxyalkyl, the hydroxyl group of which is optionally esterifiedwith C₂₋₄-alkanoyl or an amino acid residue; phenyl or benzyl, and R⁴ ishydrogen or a group forming a biolabile ester, or a physiologicallyacceptable salt thereof.
 2. A compound according to claim 1, wherein R¹is hydrogen or a group forming a biolabile ester, R² is hydrogen,C₁₋₄-alkyl or C₁₋₄-hydroxyalkyl, the hydroxyl group of which isoptionally substituted by C₂₋₄-alkanoyl, and R³ is C₁₋₄-alkyl;C₁₋₄-alkoxy-C₁₋₄-alkyl; C₁₋₄-hydroxyalkyl, which is optionallysubstituted by a second hydroxyl group and the hydroxyl groups of whichare optionally substituted by C₂₋₄-alkanoyl; C₁₋₄-alkylamino-C₁₋₄-alkyl;C₃₋₇-cycloalkyl; C₃₋₇-cycloalkyl-C₁₋₄-alkyl; phenyl-C₁₋₄-alkyl, thephenyl group of which is optionally substituted 1-2 times by C₁₋₄-alkyl,C₁₋₄-alkoxy and/or halogen; naphthyl-C₁₋₄-alkyl; C₃₋₆-oxoalkyl;phenylcarbonylmethyl, the phenyl group of which is optionallysubstituted 1-2 times by C₁₋₄-alkyl, C₁₋₄-alkoxy and/or halogen, or2-oxoazepanyl, or R² and R³ together are C₄₋₇-alkylene, the methylenegroups of which are optionally replaced 1-2 times by carbonyl, nitrogen,oxygen and/or sulfur and which are optionally substituted once byC₁₋₄-alkyl; C₁₋₄-hydroxyalkyl, the hydroxyl group of which is optionallysubstituted by C₂₋₄-alkanoyl; oxygen; phenyl or benzyl, and R⁴ ishydrogen or a group forming a biolabile ester, or a physiologicallyacceptable salt thereof.
 3. A compound according to claim 1, wherein R¹is hydrogen, ethyl, methoxyethoxymethyl,(RS)-1-[[(isopropyl)carbonyl]oxy]ethyl,(RS)-1-[[(ethyl)carbonyl]-oxy]-2-methylpropyl,(RS)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl,5-methyl-2-oxo-1,3-dioxolen-4-yl-methyl, 2-oxo-1,3-dioxolan-4-yl-methylor (RS)-1-[[(ethoxy)carbonyl]oxy]-ethyl.
 4. A compound according toclaim 1, wherein R² is hydrogen, methyl, ethyl, 2-hydroxyethyl or3-hydroxypropyl, wherein each hydroxyl group may optionally beesterified with C₂₋₄-alkanoyl or an amino acid residue.
 5. A compoundsaccording to claim 1, wherein R³ is isopropyl; methoxyethyl;2-hydroxyethyl or 3-hydroxypropyl, each hydroxyl group optionally beingesterified with C₂₋₄-alkanoyl or an amino acid residue;3-acetyloxy-n-propyl; cyclopropylmethyl; 2-methoxybenzyl,4-methoxybenzyl, 4-methoxyphenylethyl, 2,4-dimethoxybenzyl;1-naphthylmethyl; 3-oxo-1,1-dimethylbutyl; phenyl-2-oxoethyl,2-(4-methoxyphenyl)-2-oxoethyl, 3-(2-oxoazepanyl),dimethylamino-n-propyl, (methyl)aminoethyl, amino-n-propyl,amino-n-butyl, and amino-n-pentyl.
 6. A compound I according to claim 1,wherein R² and R³ together are morpholine; piperidine; 4-ketopiperidine;4-hydroxypiperidine optionally esterified at the hydroxyl group withC₂₋₄-alkanoyl or an amino acid residue; piperazine or pyrrolidine.
 7. Acompound according to claim 1, wherein R⁴ is hydrogen, C₁₋₄-alkyl,p-methoxybenzyl, N,N-di-(C₀₋₄-alkyl)amino-C₁₋₆alkyl,(RS)-1-[[(isopropyl)carbonyl]oxy]ethyl,(RS)-1-[[(ethyl)carbonyl]oxy]-2-methylpropyl,(RS)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl,5-methyl-2-oxo-1,3-dioxolen-4-yl-methyl, 2-oxo-1,3-dioxolan-4-yl-methylor (RS)-1-[[(ethoxy)carbonyl]oxy]ethyl.
 8. A compound according to claim1, selected from the group consisting of:2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}4-[isopropyl(methyl)amino]-4-oxobutanoicacid;2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-(dimethylamino)-4-oxobutanoicacid;2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-(diethylamino)-4-oxobutanoicacid;2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-[(2-hydroxyethyl)(methyl)amino]4-oxobutanoicacid;2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-[(3-hydroxypropyl)(methyl)amino]-4-oxobutanoicacid;2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-(4-hydroxypiperidin-1-yl)-4-oxobutanoicacid;2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-oxo-4-[4-(L-valyloxy)piperidin-1-yl]butanoicacid;2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}4-morpholin-4-yl-4-oxobutanoicacid;2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-oxo-4-(4-oxopiperidin-1-yl)butanoicacid;4-[bis(2-hydroxyethyl)amino]-2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-oxobutanoicacid;2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-{ethyl[3-(ethylamino)propyl]amino}-4-oxobutanoicacid,2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-[[2-(dimethylamino)ethyl](methyl)amino]-4-oxobutanoicacid,4-[(3-aminopropyl)(ethyl)amino]-2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}4-oxobutanoicacid,2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-{methyl[2-(methylamino)ethyl]amino}-4-oxobutanoicacid,4-[(4-aminobutyl)(methyl)amino]-2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-oxobutanoicacid (75),4-[(4-aminobutyl)(ethyl)amino]-2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-oxobutanoicacid (76),2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}-carbonyl)cyclopentyl]methyl}-4-{methyl[3-(methylamino)propyl]amino}-4-oxobutanoicacid (77), and4-[(5-aminopentyl)(methyl)amino]-2-{[1-({[1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-oxobutanoicacid (78), or a biolabile ester or physiologically acceptable saltthereof.
 9. A compound according to claim 1, wherein the chiral carbonatom bearing the amide side chain in position 3 of the benzazepineskeleton is in the “S” configuration.
 10. A pharmaceutical compositioncomprising a compound according to claim 1, and at least onepharmaceutical carrier or excipient.
 11. A method of treating orinhibiting a cardiovascular disorder or disease in a patient, saidmethod comprising administering to said patient a pharmaceuticallyeffective amount of a compound according to claim
 1. 12. A methodaccording to claim 11, wherein said cardiovascualr disorder or diseaseis selected from the group consisting of congestive heart failure, andprimary and secondary hypertension.
 13. A method of treating orinhibiting sexual disfunction in a patient, said method comprisingadministering to said patient an effective sexual function enhancingamount of a compound according to claim
 1. 14. A method according toclaim 13, wherein said compound inhibits neutral endopeptidase and humansoluble endopeptidase.
 15. A method according to claim 13, wherein saidsexual dysfunction is female sexual dysfunction.
 16. A method accordingto claim 13, wherein said sexual dysfunction is male sexual dysfunction.17. A method according to claim 13, wherein the sexual dysfunction isselected from the group consisting of erectile dysfunction, ejaculatorydisorders and desire disorders.
 18. A method according to claim 17,wherein said sexual dysfunction is erectile dysfunction.
 19. A method oftreating or inhibiting an adverse condition associated with apoptosis ina patient, said method comprising administering to said patient apharmaceutically effective amount of a compound according to claim 1.20. A method according to claim 19, wherein said adverse condition isselected from the group consisting of neurodegenerative disorders,gastrointestinal disorders, acute and chronic pancreatitis, hepaticdiseases; joint-diseases; immuno-suppression or immunodeficiency;myelodysplasia; dermatological diseases; diseases of the inner ear; andtransplantation disorders.
 21. A method according to claim 19, whereinsaid adverse condition is a neurodegenerative disorder selected from thegroup consisting of ischemic stroke, cerebral ischemia, traumatic braininjury, acute disseminated encephalomyelitis, amyotrophic lateralsclerosis (ALS), retinitis pigmentosa, mild cognitive impairment,Alzheimer's disease, Pick's disease, senile dementia, progressivesupranuclear palsy, subcortical dementias, Wilson disease, multipleinfarct disease, arteriosclerotic dementia, AIDS associated dementia,cerebellar degeneration, spinocerebellar degeneration syndromes,Friedreichs ataxia, ataxia telangiectasia, epilepsy related braindamage, spinal cord injury, restless legs syndrome, Huntington'sdisease, Parkinson's disease, striatonigral degeneration, cerebralvasculitis, mitochondrial encephalo-myopathies, neuronal ceroidlipofuscinosis, spinal muscular atrophies, lysosomal storage disorderswith central nervous system involvement, leukodystrophies, urea cycledefect disorders, hepatic encephalopathies, renal encephalopathies,metabolic encephalopathies, porphyria, bacterial or viral meningitis andmeningoencephalitis, prion diseases, poisonings with neurotoxiccompounds, Guillain Barre syndrome, chronic inflammatory neuropathies,polymyositis, dermatomyositis, and radiation-induced brain damage.
 22. Amethod according to claim 19, wherein said adverse condition is agastrointestinal disorder selected from the group consisting ofirritable bowel disease, inflammatory bowel disease, Crohn's disease,ulcerative colitis, coeliac disease, Helicobacter pylori gastritis,infectious gastritides, necrotizing enterocolitis, pseudomembranousenterocolitis, radiation-induced enterocolitis, and lymphocyticgastritis.
 23. A method according to claim 19, wherein said adversecondition is a hepatic disease selected from the group consisting ofalcoholic hepatitis, viral hepatitis, metabolic hepatitis, autoimmunehepatitis, radiation-induced hepatitis, liver cirrhosis, hemolyticuremic syndrome, glomerulonephritis, lupus nephritis, and viralfulminant hepatitis.
 24. A method according to claim 19, wherein saidadverse condition is a joint disease selcecte from the group consistingof trauma and osteoarthritis.
 25. A method according to claim 19,wherein said adverse condition is an autoimmune disease selected fromthe group consisting of idiopathic inflammatory myopathy, chronicneutropenia, thrombotic thrombocytopenic purpura, rheumatoid arthritis,idiopathic thrombocytopenic purpura, autoimmune haemolytic syndromes,antiphospholipid antibody syndromes, myocarditis, multiple sclerosis,relapsing-remitting multiple sclerosis, secondary progressive multiplesclerosis, primary progressive multiple sclerosis, progressive relapsingmultiple sclerosis, acute multiple sclerosis, benign relapsing multiplesclerosis, asymptomatic multiple sclerosis, neuromyelitis optica(Devic's syndrome), lymphocytic hypophysitis, Grave's disease, Addison'sdisease, hypoparathyroidism, type 1 diabetes, systemic lupuserythematodes, pemphigus vulgaris, bullous pemphigoid, psoriaticarthritis, endometriosis, autoimmune orchitis, autoimmune erectiledysfunction, sarcoidosis, Wegener's granulomatosis, autoimmune deafness,Sjögren's disease, autoimmune uveoretinitis, interstitial cystitis,Goodpasture's syndrome and fibromyalgia.
 26. A method according to claim19, wherein said adverse condition is aplastic anemia.
 27. A methodaccording to claim 19, wherein said adverse condition is adermatological disease selected from the group consisting of pemphigousvulgaris, dermatomyositis, atopic dermatitis, Henoch-Schonlein purpura,acne, systemic sclerosis, seborrhoeic keratosis, cutaneous mastocytosis,chronic proliferative dermatitis, dyskeratosis, scleroderma,interstitial granulomatous dermatitis, psoriasis, bacterial infectionsof the skin, dermatomycoses, lepra, cutaneous leishmaniasis, vitiligo,toxic epidermal necrolysis, Steven Johnson syndrome, sebaceous adenoma,alopecia, photodamage of the skin, lichen sclerosus, acute cutaneouswounds, incontinentia pigmenti, thermal damage of the skin,exanthematous pustulosis, lichenoid dermatosis, cutaneous allergicvasculitis, and cytotoxic dermatitis.
 28. A method according to claim19, wherein said adverse condition is a disease of the inner earselected from the group consisting of acoustic trauma-induced auditoryhair cell death and hearing loss, aminoglycoside induced auditory haircell death and hearing loss, ototoxic drug-induced hearing loss,perilymphatic fistula, cholesteatoma, cochlear or vestibular ischemia,Meniere's disease, radiation-induced hearing loss, hearing loss inducedby bacterial or viral infections, and idiopathic hearing loss.
 29. Amethod according to claim 19, wherein said adverse condition is atransplantation disorder selected from the group consisting ofgraft-versus-host disease, acute and chronic rejection of heart-, lung-,kidney-, skin-, corneal-, bone marrow- or liver-transplants; woundhealing and tissue rejection.
 30. A method of preparing a compoundcorresponding to formula I:

wherein R¹ is hydrogen or a group forming a biolabile ester, R² ishydrogen, C₁₋₄-alkyl or C₁₋₄-hydroxyalkyl, the hydroxyl group of whichis optionally esterified with C₂₋₄-alkanoyl or an amino acid residue,and R³ is C₁₋₄-alkyl; C₁₋₄-alkoxy-C₁₋₄-alkyl; C₁₋₄-hydroxyalkyl, whichis optionally substituted by a second hydroxyl group and the hydroxylgroups of which are each optionally esterified with C₂₋₄-alkanoyl or anamino acid residue; (C₀₋₄-alkyl)₂amino-C₁₋₆alkyl; C₃₋₇-cycloalkyl;C₃₋₇-cycloalkyl-C₁₋₄-alkyl; phenyl-C₁₋₄-alkyl, the phenyl group of whichis optionally substituted once or twice by C₁₋₄-alkyl, C₁₋₄-alkoxy orhalogen; naphthyl-C₁₋₄-alkyl; C₃₋₆-oxoalkyl; phenylcarbonylmethyl, thephenyl group of which is optionally substituted once or twice byC₁₋₄-alkyl, C₁₋₄-alkoxy or halogen, or 2-oxoazepanyl, or R² and R³together are C₄₋₇-alkylene, the methylene groups of which are optionallyreplaced once or twice by carbonyl, nitrogen, oxygen or sulfur and whichare optionally substituted once by hydroxy, which in turn is optionallyesterified with C₂₋₄-alkanoyl or an amino acid residue; C₁₋₄-alkyl;C₁₋₄-hydroxyalkyl, the hydroxyl group of which is optionally esterifiedwith C₂₋₄-alkanoyl or an amino acid residue; phenyl or benzyl, and R⁴ ishydrogen or a group forming a biolabile ester, or a physiologicallyacceptable salt thereof; said method comprising: reacting a compoundcorresponding to formula II:

wherein R¹⁰¹ and R⁴⁰¹, independently of each other, are each anacid-protecting group, with a compound corresponding to formula III:

wherein R² and R³ have the above meanings, and if R² or R³ contain freehydroxyl groups, optionally reacting the free hydroxyl groups with acompound corresponding to formula IV:C₁₋₃—C(O)—X  IV wherein X stands for a leaving group, or with an aminoacid derivative protected by a suitable protective group, and if atleast one of R¹⁰¹ and R⁴⁰¹ is not a desired biolabile ester forminggroup, or if at least one of R² and R³ comprises a protective group,cleaving off such groups to release an acid group, and thereafterconverting the acid group to a biolabile ester, and optionallyconverting an acid or base of Formula I into a correspondingphysiologically acceptable salt, or optionally coverting a salt offormula I into a corresponding free acid or base.
 31. A compoundcorresponding to formula II:

wherein R¹⁰¹ is an acid-protecting group and R⁴⁰¹ is an acid-protectinggroup.